WO2022165263A1 - Compositions et procédés de traitement d'infections bactériennes - Google Patents

Compositions et procédés de traitement d'infections bactériennes Download PDF

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Publication number
WO2022165263A1
WO2022165263A1 PCT/US2022/014429 US2022014429W WO2022165263A1 WO 2022165263 A1 WO2022165263 A1 WO 2022165263A1 US 2022014429 W US2022014429 W US 2022014429W WO 2022165263 A1 WO2022165263 A1 WO 2022165263A1
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WIPO (PCT)
Prior art keywords
agent
individual
day
bacterial infection
tissue
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PCT/US2022/014429
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English (en)
Inventor
Spencer GORDON
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Uqora, Inc.
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Publication of WO2022165263A1 publication Critical patent/WO2022165263A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Urinary tract infections are among the most common bacterial infections, with an associated annual cost exceeding $1 billion in the United States. Antibiotics are the standard treatment option for UTIs. Unfortunately, in many instances, out-patient antibiotic therapy for UTI leads to chronic and persistent UTI, such as, for example, recurring and imbedded UTI. These persistent UTIs most often develop as a result of antibiotic resistance. As evidence, while severe UTI hospitalizations has decreased, the incidence of UTI hospitalizations has increased. Therefore, a rise in antibiotic resistance is leading to persistent UTIs, which, in many instances, require re-hospitalization and long-term in-patient therapy (e.g., using antibiotics) to clear up recurring and/or imbedded UTIs. An improved treatment that lessens the growing burden of persistent UTIs is needed.
  • urinary tract infections recur due to underlying (bacterial) infection (e.g., as determined by presence or threshold levels of bacteria in the urine) of bladder and/or kidney tissue.
  • bacterial infection e.g., as determined by presence or threshold levels of bacteria in the urine
  • provided herein are methods of and compositions for treating, inhibiting, or reducing incidences of bladder and/or kidney infection.
  • such therapies are provided in a first instances, such as in the treatment of a first (e.g., acute) urinary tract infection, e.g., the therapy inhibiting or preventing the first (e.g., acute) urinary tract infection from infecting kidney and/or bladder tissue (which could, in some instances, result in urinary tract reinfection (persistent urinary tract infection or secondary urinary tract infection, such as, for example, recurring UTI and imbedded UTI)).
  • therapies and/or compositions provided herein are used in treating infection of a urinary tract tissue, such as infection of the bladder and/or kidney.
  • therapies and/or compositions provided herein are used in treating infection of a urinary tract tissue, such as infection of the bladder and/or kidney, and in inhibiting or preventing secondary urinary tract infections.
  • such therapies are provided in (e.g. used in the treatment of) a secondary urinary tract infection, e.g., the therapy inhibiting or preventing the first urinary tract infection from infecting kidney and/or bladder tissue (which could, in some instances, result in urinary tract reinfection (persistent urinary tract infection or secondary urinary tract infection, such as, recurring UTI and/or imbedded UTI)).
  • a bacterial infection e.g., an acute bacterial infection, a persistent bacterial infection, a recurring bacterial infection, an imbedded bacterial infection, or the like
  • a bacterial infection e.g., an acute bacterial infection, a persistent bacterial infection, a recurring bacterial infection, an imbedded bacterial infection, or the like
  • a uropathogenic E e.g., a uropathogenic E.
  • UPEC coli coli infection
  • tissue of the urinary tract e.g., bladder tissue, kidney tissue, ureter tissue, or the like
  • an individual in need thereof e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection) (e.g., of bladder tissue, kidney tissue, ureter tissue, or the like)
  • administering e.g., orally administering
  • a therapeutically effective amount of one or more agent e.g., that targets and reduces (e.g., eliminates) the bacterial infection of the urinary tract tissue in the individual (e.g., by decreasing iron availability to the bacteria (e.g., UPEC)
  • agent e.g., that targets and reduces (e.g., eliminates) the bacterial infection of the urinary tract tissue in the individual (e.g., by decreasing iron availability to the bacteria (e.g., UPEC)
  • the one or more agent has low (e.g., minimal to no) inhibitory activity on bacterial (e.g., UPEC) growth and/or survivability in the urine of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection)).
  • bacterial e.g., UPEC
  • survivability in the urine of the individual in need thereof e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection)).
  • the one or more agent inhibits bacterial (e.g., UPEC) growth and/or survivability in urinary tract tissue (e.g., bladder tissue, kidney tissue, ureter tissue, or the like) of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection) (e.g., of bladder tissue, kidney tissue, ureter tissue, or the like)).
  • urinary tract tissue e.g., bladder tissue, kidney tissue, ureter tissue, or the like
  • the bacterial infection e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection
  • the imbedded bacterial infection e.g., of bladder tissue, kidney tissue, ureter tissue, or the like
  • the one or more agent has low (e.g., minimal to no) inhibitory activity on bacterial (e.g., UPEC) growth and/or survivability in the urine and (selectively) inhibits bacterial (e.g., UPEC) growth and/or survivability in urinary tract tissue (e.g., bladder tissue, kidney tissue, ureter tissue, or the like) of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection) (e.g., of bladder tissue, kidney tissue, ureter tissue, or the like)).
  • bacterial infection e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection
  • a bacterial infection e.g., treating an active bacterial infection or preventing a (e.g., first or reoccurring) bacterial infection) (e.g., an acute bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection) (e.g., of bladder tissue and/or kidney tissue) in an individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection) (e.g., of bladder tissue and/or kidney tissue)).
  • a bacterial infection e.g., treating an active bacterial infection or preventing a (e.g., first or reoccurring) bacterial infection
  • an acute bacterial infection e.g., a recurring bacterial infection, or an imbedded bacterial infection
  • an imbedded bacterial infection e.g., of bladder tissue and/or kidney tissue
  • a method for reducing the incidence of a bacterial infection e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more
  • a bacterial infection e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more
  • an acute bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection e.g., of bladder tissue and/or kidney tissue
  • an imbedded bacterial infection e.g., of bladder tissue and/or kidney tissue
  • a method for promoting or maintaining urinary health e.g., of bladder tissue and/or kidney tissue
  • urinary health e.g., of bladder tissue and/or kidney tissue
  • a bacterial infection e.g., an acute bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection
  • a bacterial infection e.g., an acute bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection
  • a method for reducing the severity of a bacterial infection e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more
  • a bacterial infection e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more
  • an acute bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection e.g., of bladder tissue and/or kidney tissue
  • an imbedded bacterial infection e.g., of bladder tissue and/or kidney tissue
  • the individual is suffering from a (e.g., mild, acute, or chronic) bacterial infection of urinary tract tissue. In some embodiments, the individual is not suffering from a (e.g., mild, acute, or chronic) bacterial infection of urinary tract tissue.
  • the first agent and/or the second agent are administered to the individual prophylactically. In some embodiments, the individual has previously suffered from one or more bacterial infection of urinary tract tissue. In some embodiments, the individual is susceptible to (e.g., developing) a bacterial infection of urinary tract tissue.
  • the bacterial infection is a bacterial infection of ureter tissue, urethral tissue, bladder tissue, and/or kidney tissue of the individual in need thereof. In some embodiments, the bacterial infection is a bacterial infection of bladder tissue and/or kidney tissue of the individual in need thereof.
  • the bacterial infection is an acute bacterial infection, a persistent bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection.
  • the individual is suffering from an acute bacterial infection (e.g., of the kidney and/or bladder of the individual).
  • the individual is suffering from a persistent bacterial infection (e.g., of the kidney and/or bladder of the individual).
  • a persistent bacterial infection e.g., of the kidney and/or bladder of the individual.
  • the individual is suffering from an imbedded bacterial infection (e.g., of the kidney and/or bladder of the individual).
  • an imbedded bacterial infection e.g., of the kidney and/or bladder of the individual.
  • the individual is suffering from a recurring bacterial infection (e.g., of the kidney and/or bladder of the individual). In some embodiments, the individual has suffered from more than one bacterial infection (e.g., of the kidney (tissue) and/or the bladder (tissue)) within a year (e.g., within six months, within one month, within two weeks, or within one week) of a first bacterial infection (e.g., of the kidney (tissue) and/or the bladder (tissue)). [0017] In some embodiments, the individual is suffering from a bacterial infection (e.g., of the kidney and/or bladder of the individual) secondary to or subsequent to a urinary tract infection (UTI).
  • UTI urinary tract infection
  • the method comprises administering (e.g., orally administering) to the individual an effective amount of one or more agent on one or more day (e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at least two days after, at least three days after, at least four days after, or at least 7 days after) the first day)).
  • administering e.g., orally administering
  • the method comprises administering (e.g., orally administering, such as in combination with a second agent) a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof) (e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at least two days after, at least three days after, at least four days after, or at least 7 days after) the first day)).
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a pharmaceutically acceptable salt or solvate thereof e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at least two days after, at least three days after, at least four days after, or at least
  • the first agent is a catechin.
  • the catechin is epigallocatechin gallate (EGCG), or a pharmaceutically acceptable salt or solvate thereof.
  • the method comprises administering (e.g., orally administering, such as in combination with a first agent) to the individual an effective amount of a second agent (e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))) (e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at least two days after, at least three days after, at least four days after, or at least 7 days after) the first day)).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a second day e.g., the
  • the second agent is an alkaline salt.
  • the alkaline salt is a citrate salt (e.g., potassium citrate or sodium citrate).
  • the citrate salt is potassium citrate.
  • the method comprises administering (e.g., orally administering) to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof) and a second agent (e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))) (e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at
  • the method comprises administering (e.g., orally administering) to the individual an effective amount of another agent (e.g., an antibiotic) in combination with a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof) and/or a second agent (e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))) (e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at least two days after, at least three days after, at least four days after, or at least 7 days after) the first day)).
  • a first agent e.g., a catechin (e.g., epigallocate
  • the method comprises administering (e.g., orally administering) to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof) and a second agent (e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))) with another agent (e.g., an antibiotic) (e.g., on a first day and a second day (e.g., the second day being at least one day after (e.g., at least two days after, at least three days after, at least four days after, or at least 7 days after) the first day)).
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (
  • the effective amount of the first agent and, optionally, the second agent is administered at least once daily (e.g., for at least two days (e.g., at least daily for a week (e.g., at least three times per day for three to seven days), at least daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month)).
  • at least once daily e.g., for at least two days (e.g., at least daily for a week (e.g., at least three times per day for three to seven days), at least daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month).
  • the effective amount of the buffering agent and, optionally, the catechin is administered at least once daily (e.g., for at least two days (e.g., at least daily for a week (e.g., at least three times per day for three to seven days), at least daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month)).
  • at least once daily e.g., for at least two days (e.g., at least daily for a week (e.g., at least three times per day for three to seven days), at least daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month).
  • the effective amount of the first agent and the second agent are administered at least once daily (e.g., for at least two days (e.g., at least daily for a week (e.g., at least three times per day for three to seven days), at least daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month)).
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual (e.g., at least once daily) is sufficient to reduce the amount of pathogenic bacteria (e.g., pathogenic E. Coli (e.g., uropathogenic E. Coli (UPEC))) in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • pathogenic bacteria e.g., pathogenic E. Coli (e.g., uropathogenic E. Coli (UPEC)
  • UPEC uropathogenic E. Coli
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual (e.g., at least once daily) is sufficient to prevent the growth or viability of pathogenic bacteria (e.g., pathogenic E. Coli (e.g., uropathogenic E. Coli (UPEC))) in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • pathogenic bacteria e.g., pathogenic E. Coli (e.g., uropathogenic E. Coli (UPEC)
  • UPEC uropathogenic E. Coli
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual is sufficient to prevent (e.g., a reoccurring, a chronic, and/or the like) bacterial infection (e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more) in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual is sufficient to reduce the viability of the bacteria of the bacterial infection (e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more) in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual is sufficient to reduce the incidence of bacterial infection (e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more) in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual is sufficient to reduce the recurrence of bacterial infection (e.g., by at least 25% or more, such as, for example, by 25% or more, 50% or more, or 75% or more) in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the one or more agent (e.g., the first agent and/or the second agent) administered to the individual is sufficient to protect (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof from a bacterial infection (e.g., of the bladder (tissue) and/or the kidney (tissue)).
  • a bacterial infection e.g., of the bladder (tissue) and/or the kidney (tissue)
  • the method comprises maintaining a therapeutically effective amount of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) and/or the second agent, or a pharmaceutically acceptable salt or solvate thereof, in the individual (e.g., in the kidney (tissue) and/or bladder (tissue) of the individual).
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)
  • the second agent e.g., a pharmaceutically acceptable salt or solvate thereof
  • the effective amount of the first agent administered to the individual is sufficient to maintain (e.g., in the bladder and/or the kidney of the individual) a (e.g., therapeutically effective) concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) of at least 1 micromolar (pM) (e.g., 1 pM or more, 5 pM or more, or 10 pM or more) in the (e.g., urine of) the individual.
  • a concentration of the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)
  • pM micromolar
  • the effective amount of the second agent administered to the individual is sufficient to maintain (e.g., in the bladder and/or the kidney of the individual) a pH of at least 6 (e.g., 6 or more, 6.1 or more, 6.2 or more, 6.3 or more, 6.4 or more, or 6.5 or more) in the (e.g., urine of) the individual.
  • a pH of at least 6 e.g., 6 or more, 6.1 or more, 6.2 or more, 6.3 or more, 6.4 or more, or 6.5 or more
  • the effective amount of the first agent administered to the individual is sufficient to maintain (e.g., in the bladder and/or the kidney of the individual) a concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) of at least 1 micromolar (pM) (e.g., 1 pM or more, 5 pM or more, or 10 pM or more) and the effective amount of the second agent administered to the individual is sufficient to maintain (e.g., in the bladder and/or the kidney of the individual) a pH of at least 6 (e.g., 6 or more, 6.1 or more, 6.2 or more, 6.3 or more, 6.4 or more, or 6.5 or more).
  • pM micromolar
  • the first agent e.g., the catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the catechin e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof is administered to the individual at a dose of more than or equal to 100 mg/dose (e.g., 100-1,000 mg/dose, such as 200-600 mg/dose, such as 400 mg/dose) (e.g., three times per day (e.g., for 3 to 7 days)).
  • 100 mg/dose e.g., 100-1,000 mg/dose, such as 200-600 mg/dose, such as 400 mg/dose
  • three times per day e.g., for 3 to 7 days
  • the first agent e.g., the catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the catechin e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof is administered to the individual at a dose of about 200 mg/dose to about 600 mg/dose (e.g., three times per day (e.g., for 3 to 7 days)).
  • a total daily dose of the first agent e.g., the catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the catechin e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof is administered to the individual at an amount of more than or equal to 100 milligrams (mg)/day (e.g., 100-5,000 mg/day, such as 600-1,800 mg/day, such as 1,200 mg/day).
  • the first agent e.g., the catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the catechin e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof is administered to the individual at a dose of about 600 mg/day to about 1,800 mg/day.
  • the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • 1 g/dose e.g., 1-25 g/dose, such as 2-6 g/dose, such as 4 g/dose
  • 3 times per day e.g., for 3 to 7 days
  • the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • the individual is administered to the individual at a dose of about 2 g/dose to about 6 g/dose (e.g., three times per day (e.g., for 3 to 7 days)).
  • a total daily dose of the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))) is administered to the individual at an amount of more than or equal to 1 gram (g)/day (e.g., 1-50 g/day, such as 6-18 g/day, such as 12 g/day).
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • 1 gram (g)/day e.g., 1-50 g/day, such as 6-18 g/day, such as 12 g/day.
  • the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • the first agent e.g., the catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • the buffering agent e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • the first agent e.g., the catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))
  • the second agent e.g., the buffering agent (e.g., the alkaline salt (e.g., the citrate salt (e.g., potassium citrate or sodium citrate) or the carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))
  • the first agent and/or the second agent is administered as an oral formulation to the individual in need thereof.
  • the oral formulation is in a solid form or a liquid form.
  • a pharmaceutical composition e.g., an oral dosage form
  • a buffering agent e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a catechin e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • composition e.g., an oral dosage form
  • EGCG epigallocatechin gallate
  • the pharmaceutical composition is an oral dosage form.
  • the oral dosage form is a solid form or a liquid form.
  • the pharmaceutical composition is a powder (e.g., to be mixed with a liquid).
  • the pharmaceutical composition is a pre-mixed, liquid for oral consumption.
  • the pharmaceutical composition further comprises an excipient.
  • the pharmaceutical composition further comprises an additive (e.g., a flavorant).
  • the pharmaceutical composition is a single (oral) dosage form.
  • FIG. 1 shows the bodyweight evolution of mice after administration of vehicle or a combination of compounds provided herein.
  • FIG. 2A shows the colony forming unit (CFU) of mice urine after the administration of vehicle or a combination of compounds provided herein.
  • FIG. 2B shows the CFU of mice bladder tissue after the administration of vehicle or a combination of compounds provided herein.
  • FIG. 2C shows the CFU of mice kidney tissue after the administration of vehicle or a combination of compounds provided herein.
  • FIG. 3 shows the bodyweight evolution of mice in vivo after administration of vehicle or a compound or a combination of compounds provided herein.
  • FIG. 4A shows the colony forming unit (CFU) of mice urine after the administration of vehicle, a compound provided herein, or a combination of compounds provided herein.
  • FIG. 4B shows the CFU of mice bladder tissue after the administration of vehicle, a compound provided herein, or a combination of compounds provided herein.
  • FIG. 4C shows the CFU of mice kidney tissue after the administration of vehicle, a compound provided herein, or a combination of compounds provided herein.
  • treat include reducing, alleviating, abating, ameliorating, relieving, or lessening the symptoms associated with a disease, disease sate, or indication (e.g., addiction, such as opioid addiction, or pain) in either a chronic or acute therapeutic scenario.
  • treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, or indication.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2 dimethylaminoethanol, 2 diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N ethylpiperidine, polyamine resins and the like. See Berge et al.
  • a method for treating a bacterial infection (of urinary tract tissue) in an individual in need thereof comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • a method for reducing the incidence of a bacterial infection (of urinary tract tissue) in an individual in need thereof comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • a method for reducing the severity of a bacterial infection (of urinary tract tissue) in an individual in need thereof comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • a method for managing a bacterial infection (of urinary tract tissue) in an individual in need thereof comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • a method for reducing the risk of a (e.g., chronic) bacterial infection (of urinary tract tissue) in an individual in need thereof comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • a method for inhibiting the formation of and/or reducing the presence of a biofilm on urinary tract tissue comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • the individual is suffering from a (e.g., mild, acute, or chronic) bacterial infection of urinary tract tissue. In some embodiments, the individual is not suffering from a (e.g., mild, acute, or chronic) bacterial infection of urinary tract tissue.
  • the first agent and/or the second agent are administered to the individual prophylactically. In some embodiments, the individual has previously suffered from one or more bacterial infection of urinary tract tissue. In some embodiments, the individual is susceptible to (e.g., developing) a bacterial infection of urinary tract tissue.
  • a method for promoting or maintaining urinary health (of urinary tract tissue) in an individual in need thereof comprising administering to the individual an effective amount of a first agent and, optionally, a second agent.
  • the first agent and/or the second agent are administered to the individual prophylactically.
  • the individual has previously suffered from a bacterial infection of urinary tract tissue.
  • the individual is susceptible to (e.g., developing) a bacterial infection of urinary tract tissue.
  • the bacterial infection is an acute bacterial infection, a persistent bacterial infection, a recurring bacterial infection, or an imbedded bacterial infection.
  • the bacterial infection is an acute bacterial infection of urinary tract tissue.
  • the bacterial infection is a persistent bacterial infection of urinary tract tissue.
  • the bacterial infection is recurring bacterial infection of urinary tract tissue.
  • the individual has suffered from more than one bacterial infection (e.g., of the kidney (tissue) and/or the bladder (tissue)) within a year (e.g., within six months, within one month, within two weeks, or within one week) of a first bacterial infection (e.g., of the kidney (tissue) and/or the bladder (tissue)).
  • the bacterial infection is an imbedded bacterial infection of urinary tract tissue.
  • the bacterial infection is urethritis. In some embodiments, the bacterial infection is cystitis. In some embodiments, the bacterial infection is pyelonephritis. In some embodiments, the bacterial infection originated in the urethra of the individual suffering or susceptible to the bacterial infection. In some embodiments, the bacterial infection (e.g., originating in the urethra of the individual suffering or susceptible to the bacterial infection) spread to the bladder tissue and/or kidney tissue of the individual suffering or susceptible to the bacterial infection. In some embodiments, the bacterial infection originated in the urinary tract as a result of an obstruction (e.g., in the urinary tract). In some embodiments, an obstruction in the urinary tract leads to urine back flow in the, for example, the ureters, bladder, and/or kidneys.
  • an obstruction in the urinary tract leads to urine back flow in the, for example, the ureters, bladder, and/or kidneys.
  • the individual is suffering from a bacterial infection (e.g., of the kidney and/or bladder of the individual) secondary to or subsequent to a urinary tract infection (UTI).
  • a bacterial infection e.g., of the kidney and/or bladder of the individual
  • UTI urinary tract infection
  • a method of treating a secondary infection of the urinary tract of the individual e.g., a method for treating a bacterial infection of the urinary system subsequent to a first bacterial infection of the urinary system (e.g., a second, third, fourth, fifth, or more bacterial infection of the urinary system) of the individual suffering or susceptible of a bacterial infection of the urinary system.
  • a method for protecting the individual from a bacterial infection of the urinary system e.g., subsequent to a first bacterial infection of the urinary system (e.g., a second, third, fourth, fifth, or more bacterial infection of the urinary system) of the individual susceptible of a bacterial infection of the urinary system.
  • the bacterial infection of the urinary system is a bacterial infection of the ureter, urethra, bladder, or kidney of the individual.
  • the bacterial infection of the urinary system is a bacterial infection of the bladder or kidney of the individual.
  • the bacterial infection is of urinary tract tissue.
  • the bacterial infection is a bacterial infection of (e.g., epithelial cells of) the renal pelvis (tissue), the prostate (tissue), the penile (tissue), the ureter (tissue), the urethral (tissue), the bladder (tissue), and/or the kidney (tissue), and the like, of the individual.
  • the bacterial infection is a bacterial infection of ureter tissue, urethral tissue, bladder tissue, and/or kidney tissue of the individual.
  • the bacterial infection is a bacterial infection of bladder tissue and/or kidney tissue of the individual.
  • the bacterial infection is a bacterial infection of bladder tissue of the individual. In some embodiments, the bacterial infection is a bacterial infection of kidney tissue of the individual. In some embodiments, the bacterial infection is a bacterial infection of bladder tissue and kidney tissue of the individual.
  • the method comprises administering to the individual an effective amount of the first agent and another agent. In some embodiments, the method comprises administering to the individual an effective amount of the second agent and another agent. In some embodiments, the method comprises administering to the individual an effective amount of the first agent and the second agent. In some embodiments, the method comprises administering to the individual an effective amount of the first agent, the second agent, and another agent. In some embodiments, the other agent is an antibiotic. In some embodiments, the antibiotic is a first-line antibiotic for urinary tract infections, such as, for example, nitrofurantoin, trimethoprim/sulfamethoxazole, ciprofloxacin, cephalexin, and/or fosfomycin. In some embodiments, the method comprises administering to the individual an effective amount of the first agent and the second agent subsequent to administration of an antibiotic therapy, such as, for example, a front-line antibiotic therapy.
  • an antibiotic therapy such as, for example, a front-line antibiotic therapy.
  • the therapeutically effective amount of the first agent and/or the second agent is administered as an oral formulation to the individual in need thereof.
  • the oral formulation is in a solid form or a liquid form.
  • the oral formulation is in a solid form.
  • the oral formulation is in a powder form (e.g., to be mixed with a liquid).
  • the oral formulation is in a liquid form.
  • the oral formulation is in a premixed liquid form.
  • the method comprises orally administering to the individual an effective amount of the first agent. In some embodiments, the method comprises orally administering to the individual an effective amount of the second agent. In some embodiments, the method comprises orally administering to the individual an effective amount of the first agent and another agent. In some embodiments, the method comprises orally administering to the individual an effective amount of the second agent and another agent. In some embodiments, the method comprises orally administering to the individual an effective amount of the first agent and the second agent. In some embodiments, the method comprises orally administering to the individual an effective amount of the first agent, the second agent, and another agent. In some embodiments, the other agent is an antibiotic.
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to reduce the amount of pathogenic bacteria in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof. In some embodiments, the effective amount of the first agent and/or the second agent administered to the individual is sufficient to inhibit or reduce the ability of pathogenic bacteria (e.g., pathogenic E. Coli (e.g., Uropathogenic E.
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to reduce the amount of (urinary) iron (e.g., available to pathogenic bacteria in the urine) and increase (urinary) pH in the urinary tract tissue of (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • a siderophore e.g., a ferric iron complex, such as, for example, a high-affinity iron-chelating compound, such as, for example, a catechin as described elsewhere herein.
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to reduce the amount of (urinary) iron (e.g., available to pathogenic bacteria in the urine) and increase (urinary) pH in the urinary tract tissue of (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the bacterial infection is of a pathogenic bacteria.
  • the pathogenic bacteria is pathogenic E. Coli.
  • the pathogenic bacteria is uropathogenic E. Coli (UPEC).
  • the one or more agent reduces bacterial (e.g., UPEC) growth and/or survivability in the individual (e.g., of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection)).
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent reduces bacterial (e.g., UPEC) growth and/or survivability in the individual (e.g., of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection)).
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) reduces bacterial (e.g., UPEC) growth and/or survivability in the urine, kidney tissue, and/or bladder tissue of the individual.
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)
  • the second agent reduces bacterial (e.g., UPEC) growth and/or survivability in the urine, kidney tissue, and/or bladder tissue of the individual.
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) reduces bacterial (e.g., UPEC) growth and/or survivability in the urine of the individual.
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent reduces bacterial (e.g., UPEC) growth and/or survivability in the urine of the individual.
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) reduces bacterial (e.g., UPEC) growth and/or survivability in the kidney tissue of the individual.
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent reduces bacterial (e.g., UPEC) growth and/or survivability in the kidney tissue of the individual.
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) reduces bacterial (e.g., UPEC) growth and/or survivability in the bladder tissue of the individual.
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent reduces bacterial (e.g., UPEC) growth and/or survivability in the bladder tissue of the individual.
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) reduces bacterial (e.g., UPEC) growth and/or survivability in the kidney tissue and the bladder tissue of the individual.
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent reduces bacterial (e.g., UPEC) growth and/or survivability in the kidney tissue and the bladder tissue of the individual.
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent has low (e.g., minimal to no) inhibitory activity on bacterial (e.g., UPEC) growth and/or survivability in the urine (e.g., of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection)) (FIG. 2A and FIG. 4A).
  • the first agent e.g., or an active form thereof (e
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) inhibits bacterial (e.g., UPEC) growth and/or survivability in urinary tract tissue (e.g., bladder tissue, kidney tissue, ureter tissue, or the like) (e.g., of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection) (e.g., of bladder tissue, kidney tissue, ureter tissue, or the like))) (FIG.
  • the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or
  • the one or more agent e.g., the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent) has low (e.g., minimal to no) inhibitory activity on bacterial (e.g., UPEC) growth and/or survivability in the urine and (selectively) inhibits bacterial (e.g., UPEC) growth and/or survivability in urinary tract tissue (e.g., bladder tissue, kidney tissue, ureter tissue, or the like) of the individual in need thereof (e.g., in an individual suffering from or susceptible to the bacterial infection (e.g., the acute bacterial infection, the recurring bacterial infection, or the imbedded bacterial infection) (e.g., of bladder tissue, kidney tissue, ureter
  • the one or more agent is an active form of the first agent (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent.
  • the first agent e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the (urinary) concentration of the active form of the first agent (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent is not sufficient to inhibit or reduce bacterial (e.g., UPEC) growth and/or survivability in the urine (e.g., of the individual).
  • the first agent e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent is not sufficient to inhibit or reduce bacterial (e.g., UPEC) growth and/or survivability in the urine (e.g., of the individual).
  • the (urinary) concentration of the active form of the first agent (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like) and/or the second agent is sufficient to inhibit or reduce bacterial (e.g., UPEC) growth and/or survivability in the urinary tract tissue (e.g., of the individual).
  • the first agent e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like
  • the second agent is sufficient to inhibit or reduce bacterial (e.g., UPEC) growth and/or survivability in the urinary tract tissue (e.g., of the individual).
  • a urinary tract infection in mice is established and then mice are treated with a therapeutically effective amount of Compound 1 and Compound 2.
  • Colony forming units (CFU) in the bladder were statistically significantly lower in a group treated with Compound 1 and Compound 2 than in control group (FIG. 2B).
  • results obtained for kidneys and urine revealed similar bacterial loads in groups vehicle and treated with the compounds combination (FIG. 2 A & FIG. 2C).
  • a combination provided herein penetrates into bladder tissue and inhibits and/or reduces pathogenic bacterial growth in the bladder tissue (in vivo), while not affecting pathogenic bacterial growth in urine or kidney tissue (in vivo).
  • mice are treated with a therapeutically effective amount of Compound 3, Compound 4, or a combination thereof three times daily.
  • Colony forming units (CFU) in the bladder and kidney were statistically significantly lower in a group treated with Compound 3 and Compound 4 than in control group (FIG. 4B and FIG. 4C).
  • results obtained for urine revealed similar bacterial loads in groups vehicle and treated with the compounds and combinations thereof (FIG. 4A).
  • a combination provided herein penetrates into bladder and kidney tissue and inhibits and/or reduces pathogenic bacterial growth in the bladder and kidney tissue (in vivo), while not affecting pathogenic bacterial growth in urine (in vivo).
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to prevent a chronic bacterial infection in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to reduce the viability of the bacterial infection in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to reduce the incidence of the bacterial infection in (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof.
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to reduce bacterial infection recurrence in (e.g., the kidney tissue and/or bladder tissue of) (e.g., for at least one week (for four to eight weeks) following administration of the first agent and/or the second agent (e.g., such as in combination with another agent (e.g., an antibiotic)) (e.g., or a regimen thereof, such as a regimen described herein)) the individual in need thereof.
  • another agent e.g., an antibiotic
  • the effective amount of the first agent and/or the second agent administered to the individual is sufficient to protect (e.g., the kidney tissue and/or bladder tissue of) the individual in need thereof from a bacterial infection (e.g., of the bladder (tissue) and/or the kidney (tissue)).
  • a bacterial infection e.g., of the bladder (tissue) and/or the kidney (tissue)
  • the first agent is an iron chelator. In some embodiments, the first agent chelates iron in the urine. In some embodiments, the first agent is a siderocalin (SCN) cofactor. In some embodiments, the first agent increases urinary phenolic acid concertation (e.g., in the individual). In some embodiments, the first agent contains a gallate moiety. In some embodiments, the first agent increases the urinary concentration of pyrogallol, catechol (e.g., pyrocatechol, 4-methylcatechol, caffeic acid, or the like), or the like. In some embodiments, the first agent increases the urinary concentration of pyrogallol.
  • catechol e.g., pyrocatechol, 4-methylcatechol, caffeic acid, or the like
  • the first agent increases the urinary concentration of pyrogallol.
  • the first agent increases the urinary concentration of gallic acid, gallocatechin gallate (GCG), catechin gallate (GC), caffeic acid, epigallocatechin (EGC), epicatechin gallate (ECG), propyl gallate, 3- methylcatechol, 4-methylcatechol, or the like. In some embodiments, the first agent increases the urinary concentration of gallic acid, gallocatechin gallate (GCG), catechin gallate (GC), caffeic acid, epigallocatechin (EGC), epicatechin gallate (ECG), or the like. In some embodiments, the first agent is a tannin (e.g., tannic acid) or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • a tannin e.g., tannic acid
  • the first agent is a flavonoid or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the first agent is a catechin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the first agent is epigallocatechin gallate (EGCG) or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the first agent is epigallocatechin gallate (EGCG) or a pharmaceutically acceptable salt or solvate thereof.
  • the catechin is administered as a purified compound or as part of a botanical extract.
  • the second agent is a buffering agent. In some embodiments, the second agent is a base salt. In some embodiments, the second agent alkalizes urine of the individual. In some embodiments, the second agent is an alkaline salt. In some embodiments, the second agent is a citrate salt. In some embodiments, the second agent is potassium citrate or sodium citrate. In some embodiments, the second agent is potassium citrate. In some embodiments, the second agent is sodium citrate. In some embodiments, the second agent is a carbonate salt. In some embodiments, the second agent is potassium bicarbonate or sodium bicarbonate. In some embodiments, the second agent is potassium bicarbonate. In some embodiments, the second agent is sodium bicarbonate.
  • the first agent is an iron chelator and the second agent is a buffering agent.
  • the first agent is a siderocalin (SCN) cofactor and the second agent is an alkaline salt.
  • the first agent is a flavonoid or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof and the second agent is an alkaline salt.
  • the first agent is a catechin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, and the second agent is an alkaline salt.
  • the first agent is epigallocatechin gallate (EGCG), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, and the second agent is potassium citrate or sodium citrate.
  • the first agent is epigallocatechin gallate (EGCG), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, and the second agent is potassium bicarbonate or sodium bicarbonate.
  • the first compound and/or the second compound is administered to the individual in need thereof on one or more day. In some embodiments, the first compound and/or the second compound is administered to the individual in need thereof on a first day and a second day. In some embodiments, the second day is at least one day after (e.g., at least two days after, at least three days after, at least four days after, at least five days after, at least six days after, or at least seven days after) the first day.
  • the first compound and/or the second compound is administered to the individual in need thereof a third time, wherein the third time is a time between the first time and the second time or after the second time.
  • the first compound and/or the second compound is administered to the individual in need thereof a fourth time.
  • the fourth time is a time between the first and third time.
  • the fourth time is a time between the first and second time.
  • the fourth time is a time after the first time.
  • the fourth time is a time after the second time.
  • the fourth time is a time after the third time.
  • the first time, second time, third time, fourth time, and so on is on the same day.
  • the first time, second time, third time, fourth time, and so on is on a different day.
  • at least the first time and second time are on the same day.
  • at least the first time, second time, and third time are on the same day.
  • administration to an individual in need thereof occurs no more frequently than once a day (e.g., no more frequently than once every other day, no more frequently than once every third day, no more frequently than twice a week, no more frequently than once a week, no more frequently than once every two weeks, or the like).
  • administration to a subject in need thereof occurs once a day, two times per day, three times per day, four times per day, every alternate day, three times a week, twice a week, once a week, every other week, two weeks per month, three weeks per month, once a month, twice a month or three times per month.
  • administration is about once a day.
  • administration is every day for several days (e.g., every day for two days, three days, four days, five days, six days, seven days, fourteen days, thirty days, or more). In some embodiments, administration is two times per day for at least one week. In some embodiments, administration is three times per day for at least one week.
  • administration continues (e.g., several times daily (e.g., three times per day) for any suitable length of time, such as at least 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, or 3 years.
  • the effective amount of the first agent and, optionally, the second agent is administered to the individual at least once daily. In some embodiments, the effective amount of the first agent and, optionally, the second agent is administered to the individual at least once daily for at least two days. In some embodiments, the effective amount of the first agent and, optionally, the second agent is administered to the individual at least once daily for a week. In some embodiments, the effective amount of the first agent and, optionally, the second agent is administered to the individual at least three times per day for three to seven days.
  • the effective amount of the first agent and, optionally, the second agent is administered to the individual at least at least once daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month.
  • the effective amount of the buffering agent and, optionally, the catechin is administered to the individual at least once daily. In some embodiments, the effective amount of the buffering agent and, optionally, the catechin is administered to the individual at least once daily for at least two days. In some embodiments, the effective amount of the buffering agent and, optionally, the catechin is administered to the individual at least once daily for a week. In some embodiments, the effective amount of the f buffering agent and, optionally, the catechin is administered to the individual at least three times per day for three to seven days.
  • the effective amount of the buffering agent and, optionally, the catechin is administered to the individual at least at least once daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month.
  • the effective amount of the first agent and the second agent is administered to the individual at least once daily. In some embodiments, the effective amount of the first agent and the second agent is administered to the individual at least once daily for at least two days. In some embodiments, the effective amount of the first agent and the second agent is administered to the individual at least once daily for a week. In some embodiments, the effective amount of the first agent and the second agent is administered to the individual at least three times per day for three to seven days.
  • the effective amount of the first agent and the second agent is administered to the individual at least at least once daily for a month, at least every other day for a week, at least every other day for a month, at least two times a week for a month, at least once a week for a month, or at least bi-weekly for a month.
  • the first agent is administered to the individual at a dose of more than or equal to about 100 mg/dose (e.g., 100 mg/dose or more, 200 mg/dose or more, 300 mg/dose or more, 400 mg/dose or more, 500 mg/dose or more, 600 mg/dose or more, 700 mg/dose or more, 800 mg/dose or more, 900 mg/dose or more, 1,000 mg/dose or more, 2,500 mg/dose or more, or 5,000 mg/dose or more). In some embodiments, the first agent is administered to the individual at a dose of less than or equal to about 100 mg/dose (e.g., 100 mg/dose or less, 50 mg/dose or less, or 25 mg/dose or less).
  • 100 mg/dose e.g., 100 mg/dose or less, 50 mg/dose or less, or 25 mg/dose or less.
  • the first agent is administered to the individual at a dose of about 100 mg/dose to about 1,000 mg/dose (e.g., about 100 mg/dose, about 200 mg/dose, about 300 mg/dose, about 400 mg/dose, about 500 mg/dose, about 600 mg/dose, about 700 mg/dose, about 800 mg/dose, about 900 mg/dose, or about 1,000 mg/dose).
  • the first agent is administered to the individual at a dose of about 200 mg/dose to about 600 mg/dose (e.g., about 200 mg/dose, about 300 mg/dose, about 400 mg/dose, about 500 mg/dose, about 600 mg/dose).
  • the first agent is administered to the individual at a dose of about 400 mg/dose.
  • the first agent is administered to the individual three times per day. In some embodiments, the first agent is administered to the individual three times per day for two days or more, three days or more, four days or more, five days or more, six days or more, or seven days or more. In some embodiments, the first agent is administered to the individual three times per day for three to seven days. In some embodiments, the first agent is administered to the individual three times per day for three days. In some embodiments, the first agent is administered to the individual three times per day for seven days.
  • a total daily dose of the first agent is administered to the individual at an amount of more than or equal to about 100 milligrams (mg)/day (e.g., 100 mg/day or more, 200 mg/day or more, 300 mg/day or more, 400 mg/day or more, 500 mg/day or more, 600 mg/day or more, 700 mg/day or more, 800 mg/day or more, 900 mg/day or more, 1,000 mg/day or more, 2,500 mg/day or more, 5,000 mg/day or more, 10,000 mg/day or more, or 25,000 mg/day).
  • milligrams e.g., 100 mg/day or more, 200 mg/day or more, 300 mg/day or more, 400 mg/day or more, 500 mg/day or more, 600 mg/day or more, 700 mg/day or more, 800 mg/day or more, 900 mg/day or more, 1,000 mg/day or more, 2,500 mg/day or more, 5,000 mg/day or more, 10,000 mg/day or more, or 25,000 mg/day
  • a total daily dose of the first agent is administered to the individual at an amount of less than or equal to about 100 mg/day (e.g., 100 mg/day or less, 50 mg/day or less, or 25 mg/day or less). In some embodiments, a total daily dose of the first agent is administered to the individual at an amount of about 100 mg/day to about 5,000 mg/day (e.g., about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1,000 mg/day, about 2,500 mg/day, or about 5,000 mg/day).
  • a total daily dose of the first agent is administered to the individual at an amount of about 600 mg/day to about 1,800/day (e.g., about 600 mg/day, about 750 mg/day, about 900 mg/day, about 1,000 mg/day, about 1,250 mg/day, about 1,500 mg/day, or about 1,800 mg/day). In some embodiments, a total daily dose of the first agent is administered to the individual at an amount of about 1 ,200 mg/day.
  • the second agent is administered to the individual at a dose of more than or equal to about 1 g/dose (e.g., 1 g/dose or more, 2 g/dose or more, 3 g/dose or more, 4 g/dose or more, 5 g/dose or more, 10 g/dose or more, 15 g/dose or more, 20 g/dose or more, 25 g/dose or more, or 50 g/dose or more).
  • the second agent is administered to the individual at a dose of less than or equal to about 1 g/dose (e.g., 1 g/dose or less, 0.5 g/dose or less, or 0.1 g/dose or less).
  • the second agent is administered to the individual at a dose of about 1 g/dose to about 25 g/dose (e.g., about 1 g/dose, about 2 g/dose, about 3 g/dose, about 4 g/dose, about 5 g/dose, about 10 g/dose, about 15 g/dose, about 20 g/dose, or about 25 g/dose).
  • the second agent is administered to the individual at a dose of about 2 g/dose to about 6 g/dose (e.g., about 2 g/dose, about 3 g/dose, about 4 g/dose, about 5 g/dose, or about 6 g/dose).
  • the second agent is administered to the individual at a dose of about 4 g/dose. In some embodiments, the second agent is administered to the individual three times per day. In some embodiments, the second agent is administered to the individual three times per day for two days or more, three days or more, four days or more, five days or more, six days or more, or seven days or more. In some embodiments, the second agent is administered to the individual three times per day for three to seven days. In some embodiments, the second agent is administered to the individual three times per day for three days. In some embodiments, the second agent is administered to the individual three times per day for seven days.
  • a total daily dose of the second agent is administered to the individual at an amount of more than or equal to about 1 gram (g)/day (e.g., 1 g/day or more, 2 g/day or more, 3 g/day or more, 4 g/day or more, 5 g/day or more, 10 g/day or more, 15 g/day or more, 20 g/day or more, 25 g/day or more, 50 g/day or more, or 100 g/day or more).
  • g gram/day
  • a total daily dose of the second agent is administered to the individual at an amount of less than or equal to about 1 g/day (e.g., 1 g/day or less, 0.5 g/day or less, or 0.1 g/day or less). In some embodiments, a total daily dose of the second agent is administered to the individual at an amount of about 1 g/day to about 50 g/day (e.g., about 1 g/day, about 2 g/day, about 3 g/day, about 4 g/day, about 5 g/day, about 10 g/day, about 15 g/day, about 20 g/day, about 25 g/day, or about 50 g/day).
  • a total daily dose of the second agent is administered to the individual at an amount of about 6 g/day to about 18 g/day (e.g., about 6 g/day, about 7 g/day, about 8 g/day, about 9 g/day, about 10 g/day, about 11 g/day, about 12 g/day, about 13 g/day, about 14 g/day, about 15 g/day, about 16 g/day, about 17 g/day, or about 18 g/day). In some embodiments, a total daily dose of the second agent is administered to the individual at an amount of about 12 g/day.
  • the first agent is administered to the individual at a dose of more than or equal to about 100 mg/dose (e.g., 100 mg/dose or more, 200 mg/dose or more, 300 mg/dose or more, 400 mg/dose or more, 500 mg/dose or more, 600 mg/dose or more, 700 mg/dose or more, 800 mg/dose or more, 900 mg/dose or more, 1,000 mg/dose or more, 2,500 mg/dose or more, or 5,000 mg/dose or more) and the second agent is administered to the individual at a dose of more than or equal to about 1 g/dose (e.g., 1 g/dose or more, 2 g/dose or more, 3 g/dose or more, 4 g/dose or more, 5 g/dose or more, 10 g/dose or more, 15 g/dose or more, 20 g/dose or more, 25 g/dose or more, or 50 g/dose or more).
  • 100 mg/dose e.g., 100 mg/dose or more, 200 mg/dose or more
  • the first agent is administered to the individual at a dose of about 200 mg/dose to about 600 mg/dose (e.g., about 200 mg/dose, about 300 mg/dose, about 400 mg/dose, about 500 mg/dose, about 600 mg/dose) and the second agent is administered to the individual at a dose of about 2 g/dose to about 6 g/dose (e.g., about 2 g/dose, about 3 g/dose, about 4 g/dose, about 5 g/dose, or about 6 g/dose).
  • the first agent is administered to the individual at a dose of about 400 mg/dose and the second agent is administered to the individual at a dose of about 4 g/dose.
  • the first agent and the second agent are administered to the individual three times per day. In some embodiments, the first agent and the second agent are administered to the individual three times per day for two days or more, three days or more, four days or more, five days or more, six days or more, or seven days or more. In some embodiments, the first agent and the second agent are administered to the individual three times per day for three to seven days. In some embodiments, the first agent and the second agent are administered to the individual three times per day for three days. In some embodiments, the first agent and the second agent are administered to the individual three times per day for four days. In some embodiments, the first agent and the second agent are administered to the individual three times per day for five days.
  • the first agent and the second agent are administered to the individual three times per day for six days. In some embodiments, the first agent and the second agent are administered to the individual three times per day for seven days. [0109] In some embodiments, a total daily dose of the first agent is administered to the individual at an amount of more than or equal to about 100 milligrams (mg)/day (e.g., 100 mg/day or more, 200 mg/day or more, 300 mg/day or more, 400 mg/day or more, 500 mg/day or more, 600 mg/day or more, 700 mg/day or more, 800 mg/day or more, 900 mg/day or more, 1,000 mg/day or more, 2,500 mg/day or more, 5,000 mg/day or more, 10,000 mg/day or more, or 25,000 mg/day) and the second agent is administered to the individual at an amount of more than or equal to about 1 gram (g)/day (e.g., 1 g/day or more, 2 g/day or more, 3 g/day
  • a total daily dose of the first agent is administered to the individual at an amount of about 600 mg/day to about 1,800 mg/day (e.g., about 600 mg/day, about 750 mg/day, about 900 mg/day, about 1,000 mg/day, about 1,250 mg/day, about 1,500 mg/day, or about 1,800 mg/day) and the second agent is administered to the individual at an amount of about 6 g/day to about 18 g/day (e.g., about 6 g/day, about 7 g/day, about 8 g/day, about 9 g/day, about 10 g/day, about 11 g/day, about 12 g/day, about 13 g/day, about 14 g/day, about 15 g/day, about 16 g/day, about 17 g/day, or about 18 g/day).
  • about 6 g/day to about 18 g/day e.g., about 6 g/day, about 7 g/day, about 8 g/day, about 9 g
  • a total daily dose of the first agent is administered to the individual at an amount of about 1 ,200 mg/day and the second agent is administered to the individual at an amount of about 12 g/day.
  • a therapeutically effective amount of the first agent is maintained in (e.g., the urine) of the individual.
  • a therapeutically effective amount of the second agent is maintained in (e.g., the urine) of the individual.
  • a therapeutically effective amount of the first agent and the second agent is maintained in (e.g., the urine) of the individual.
  • the effective amount of the first agent administered to the individual is sufficient to maintain a therapeutically effective concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)).
  • a therapeutically effective concentration of the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)
  • the effective amount of the first agent administered to the individual is sufficient to maintain a concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) of at least 1 micromolar (pM) (e.g., 1 pM or more, 5 pM or more, 10 pM or more, 15 pM or more, 25 pM or more, or 50 pM or more) in the (e.g., urine of) the individual.
  • pM micromolar
  • the effective amount of the first agent administered to the individual is sufficient to maintain a concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) of at least 10 micromolar (pM) (e.g., 10 pM or more, 15 pM or more, 25 pM or more, or 50 pM or more) in the (e.g., urine of) the individual.
  • pM micromolar
  • the effective amount of the first agent administered to the individual is sufficient to maintain a concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) of at most 1 micromolar (pM) (e.g., 1 pM or less, 0.5 pM or less, or 0.1 pM or less) in the (e.g., urine of) the individual.
  • pM micromolar
  • the effective amount of the second agent administered to the individual is sufficient to maintain a therapeutically effective concentration of the second agent. In some embodiments, the effective amount of the second agent administered to the individual is sufficient to maintain a pH of at least 6 (e.g., 6 or more, 6.1 or more, 6.2 or more, 6.3 or more, 6.4 or more, or 6.5 or more) in the (e.g., urine of) the individual. In some embodiments, the effective amount of the second agent administered to the individual is sufficient to maintain a pH of at least 6.5 in the urine of the individual.
  • the effective amount of the first agent administered to the individual is sufficient to maintain a therapeutically effective concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) and the effective amount of the second agent administered to the individual is sufficient to maintain a therapeutically effective concentration of the second agent.
  • a therapeutically effective concentration of the first agent e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)
  • the effective amount of the second agent administered to the individual is sufficient to maintain a therapeutically effective concentration of the second agent.
  • the effective amount of the first agent administered to the individual is sufficient to maintain a concentration of the first agent (e.g., or an active form thereof (e.g., a catechol, a pyrogallol, a phenolic acid, a caffeic acid, or the like)) of at least 10 micromolar (pM) (e.g., 10 pM or more, 15 pM or more, 25 pM or more, or 50 pM or more) in the (e.g., urine of) the individual and the effective amount of the second agent administered to the individual is sufficient to maintain a pH of at least 6.5 in the urine of the individual.
  • pM micromolar
  • the bacterial infection (e.g., recurrence) of the urinary tract tissue in the individual in need thereof is decreased or eliminated for at least one week (for four to eight weeks) following administration of the first agent and/or the second agent (e.g., such as in combination with another agent (e.g., an antibiotic)).
  • the bacterial infection (e.g., recurrence) of the urinary tract tissue in the individual in need thereof is decreased or eliminated for four to eight weeks following administration of a regimen of the first agent and/or the second agent (e.g., such as a regimen described elsewhere herein).
  • a method for treating or managing a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • administering e.g., orally administering, such as in combination with the first agent
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • an alkaline salt e.g., a citrate salt (e.g., potassium citrate or sodium citrate)
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a method for reducing the incidence of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • administering e.g., orally administering, such as in combination with the first agent
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • an alkaline salt e.g., a citrate salt (e.g., potassium citrate or sodium citrate)
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a method for reducing the severity of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • administering e.g., orally administering, such as in combination with the first agent
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • an alkaline salt e.g., a citrate salt (e.g., potassium citrate or sodium citrate)
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a method for promoting or maintaining urinary health comprising: a. administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • administering e.g., orally administering, such as in combination with the first agent
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • an alkaline salt e.g., a citrate salt (e.g., potassium citrate or sodium citrate)
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a method for treating or managing a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. optionally, administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • an alkaline salt e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for reducing the incidence of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. optionally, administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for promoting or maintaining urinary health comprising: a. optionally, administering to the individual an effective amount of a first agent (e.g., a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof); and b.
  • a first agent e.g., a catechin (e.g., epigallocatechin gallate (EGCG)
  • EGCG epigallocatechin gallate
  • a second agent e.g., a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)))).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • an alkaline salt e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for treating or managing a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for reducing the incidence of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for reducing the severity of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for promoting or maintaining urinary health comprising: a. administering to the individual an effective amount of a catechin (e.g., epigallocatechin gallate (EGCG)), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a buffering agent (e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate))).
  • a buffering agent e.g., an alkaline salt (e.g., a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate)
  • a method for treating or managing a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of epigallocatechin gallate (EGCG), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate).
  • EGCG epigallocatechin gallate
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a method for reducing the incidence of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of epigallocatechin gallate (EGCG), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate).
  • EGCG epigallocatechin gallate
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a method for reducing the severity of a bacterial infection of urinary tract tissue in an individual in need thereof comprising: a. administering to the individual an effective amount of epigallocatechin gallate (EGCG), or a pharmaceutically acceptable salt or solvate thereof; and b. administering a citrate salt (e.g., potassium citrate or sodium citrate) or a carbonate salt (e.g., potassium bicarbonate or sodium bicarbonate).
  • EGCG epigallocatechin gallate
  • a citrate salt e.g., potassium citrate or sodium citrate
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • EGCG epigallocatechin gallate
  • a pharmaceutically acceptable salt or solvate thereof e.g., sodium citrate
  • a carbonate salt e.g., potassium bicarbonate or sodium bicarbonate
  • a pharmaceutical composition comprising a buffering agent (e.g., as described elsewhere herein) and a catechin (as described elsewhere herein), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof).
  • the catechin is provided in the pharmaceutical composition as a purified compound or as part of a botanical extract.
  • a pharmaceutical composition comprising potassium citrate and epigallocatechin gallate (EGCG).
  • EGCG epigallocatechin gallate
  • the pharmaceutical composition is an oral dosage form.
  • the oral dosage form is a solid form or a liquid form.
  • the oral dosage form is a solid form.
  • the solid dosage form is a pill (e.g., a tablet or a capsule), a crystalline solid, a powder, or the like.
  • the oral dosage form is a powder.
  • the oral dosage form is a liquid form.
  • the oral dosage form is a syrup, a solution, a suspension, or the like.
  • the pharmaceutical composition is a powder (e.g., to be mixed with a liquid). In some embodiments, the pharmaceutical composition is a pre -mixed, liquid for oral consumption.
  • the amount of the first agent and/or the second agent in the pharmaceutical composition is described elsewhere herein.
  • the pharmaceutical composition further comprises an excipient.
  • the pharmaceutical composition further comprises an additive (e.g., a flavorant).
  • the pharmaceutical composition is a single (oral) dosage form.
  • Example 1 Urinary tract infection murine model induced by E. coli UTI89 (first agent active form + second agent)
  • Uropathogenic Escherichia coli (UPEC, UTI89) is diluted in sterile PBS (Phosphate Buffered Saline) the day of induction to 1 x 10 7 CFU/mouse.
  • the route of administration is the intra-vesical route.
  • 2 x 50 pL of E. coli inoculum are injected in bladder after urine discharge and catheter placement in urethra.
  • 2h before intra-vesical induction the mice receive a water privation to reduce urine charge (water ad libitum 4h after the first induction). Induction is performed on animals anesthetized with isoflurane.
  • the animals are housed in ventilated and enriched plastic cages (48 x 37.5 x 21 cm) containing irradiated sawdust as a bedding material, as prescribed by the housing standards throughout the experimental phase. Mice are housed in groups maximum of 5 animals per cage on a regular light-dark cycle (at 07:00 pm the lights are off with 12:12 light-dark circle), 22 ⁇ 2 °C and at 50 ⁇ 10% relative humidity. Housing parameters are daily recorded. During the acclimation phase and experimental phase, standard diet (RM1 (E) 801492, SDS) and tap water are provided ad libitum. [0146] Animals are acclimated in an isolated room of the animal facility at least 4 days after the arrival and prior to dosing. During this period, the animals are exposed to daily visual and clinical examinations before the randomization.
  • the vehicle, Compound 1, and Compound 2 are administered by intra-vesicular route. 96h after bacterial induction, few drops of urine (around 50 pL) are collected from animals from each group. Urine samples are kept at +4°C after collection and then CFU are analyzed directly after sampling. Remaining urine samples are frozen at -80°C. After euthanasia by cervical dislocation, bladder/urethra system and kidneys are collected and kept at +4°C for bacteriology. Specimens analysis
  • Tissue samples are crushed with Precellys Lysing Kit (Bertin). Immediately after this step, the homogenates are diluted in PBS. 50pl is plated on Trypticase Soy Agar plates. All the plates are incubated 24h at 37°C. 24h after incubation, CFU (Colony Forming Unit) are counted to determine the bacterial organ load and the efficacy of treatment vs. control groups.
  • E. coli UTI89 stock solution is plated on TSA agar (100 pl/plate, 3 plates) and incubated at 37°C during 24h before infection. The day of infection, all E. coli colonies from 2 plates are collected and placed in 8 mL of PBS. The concentration of this solution is determined by Me FARLAND method (measurement of optic density at 595 nm). The solution is centrifuged (3,500 rpm, 10 minutes). E. coli suspension is diluted in PBS (1/28, 107 pl + 2,893 pl of PBS). 50 pl of this suspension is plated (TSA agar plate) and incubated (24h, 37°C) to determine the inoculum concentration (CFU/mL). The inoculum is as expected: 3.7 x 10 7 efu/mouse (as per Table 1).
  • Body weight monitoring and clinical signs [0150] Body weights are recorded every day and animals are daily observed. The first body weight evaluation corresponded to body weight before infection. The infection at DO trigger body weight reduction from DO to D3 (FIG. 1).
  • Urine is collected 4 days following the infection E. coli UTI89. At D4, no statistically significant difference was observed between the groups (FIG. 2A).
  • control group was as expected around 6 logio into the Bladder/urethral system, 4 days after the infection with E. coli UTI89. Analysis of bacterial burden in bladder has shown a statistically significant decrease about 1,9 logio following the treatment with Compound 1 and Compound 2 in combination (Welch's test **P ⁇ 0.05) (FIG. 2B).
  • Uropathogenic Escherichia coli (UPEC, UTI89) is diluted in sterile PBS (Phosphate Buffered Saline) the day of induction to 1 x 10 8 CFU/mouse.
  • the route of administration is the intra-vesical route.
  • 2 x 50 pL of E. coli inoculum are injected in bladder after urine discharge and catheter placement in urethra.
  • 2h before intra-vesical induction the mice had a water privation to reduce urine charge (water ad libitum 4h after first induction). Induction is performed on animals anesthetized with isoflurane.
  • the animals are housed in ventilated and enriched plastic cages (48 x 37.5 x 21 cm) containing irradiated sawdust as a bedding material, as prescribed by the housing standards throughout the experimental phase.
  • Mice are housed in groups maximum of 5 animals per cage on a regular light-dark cycle (at 07:00 pm the lights are off with 12:12 light-dark circle), 22 ⁇ 2 °C and at 50 ⁇ 10% relative humidity. Housing parameters are daily recorded.
  • standard diet (RM1 (E) 801492, SDS) and tap water are provided ad libitum.
  • Animals are acclimated in an isolated room of the animal facility at least 4 days after the arrival and prior to dosing. During this period, the animals are exposed to daily visual and clinical examinations before the randomization.
  • the buffer, Compound 3 and Compound 4 are administered by oral administration.
  • 96 h after induction for groups 1 to 4 the animals were anesthetized and the following samples will be collected: bladder + urethra, kidneys and urine.
  • 96h after bacterial induction, few drops of urine (around 50 pL) were collected from animals from each group in groups 1 to 4.
  • Urine samples were kept at +4°C after collection and then CFU were analyzed directly after sampling. Remaining urine samples were frozen at -80°C.
  • Tissue samples are crushed with Precellys Lysing Kit (Bertin). Immediately after this step, the homogenates are diluted in PBS. 50pl were plated on Trypticase Soy Agar plates. All the plates are incubated 24h at 37°C. 24h after incubation, CFU (Colony Forming Unit) are counted to determine the bacterial organ load and the efficacy of treatment vs. control groups. Results
  • E. coli UTI89 stock solution is plated on TSA agar (100 pl /pl ate, 3 plates) and incubated at 37°C during 24h before infection. The day of infection, all E. coli colonies from 2 plates are collected and placed in 8 mL of PBS. The concentration of this solution is determined by Me FARLAND method (measurement of optic density at 595 nm). The solution is centrifuged (3,500 rpm, 10 minutes). E. coli suspension is diluted in PBS (1/22, 134 pl + 3886 pl of PBS). 50 pl of this suspension is plated (TSA agar plate) and incubated (24h, 37°C) to determine the inoculum concentration (CFU/mL). The inoculum is as expected: 2.1 x 10 7 efu/mouse (as per Table 1).
  • Body weights are recorded every day and animals are daily observed. The first body weight evaluation corresponded to body weight before infection. The infection at DO trigger body weight reduction from DO to D3 (FIG. 3).
  • Urine is collected 4 days following the infection E. coli UTI89. At D4, no statistically significant difference was observed between the groups (FIG. 4A).
  • control group was as expected around 6 logio into the Bladder/urethral system, 4 days after the infection with E. coli UTI89. Analysis of bacterial burden in bladder has shown a statistically significant decrease about 2,0 logio following the treatment with Compound 3 alone, Compound 4 alone, or Compound 3 in combination with Compound 4 (FIG. 4B).

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Abstract

L'invention concerne des procédés et des compositions pour le traitement, la gestion et la protection contre une infection bactérienne du tissu du tractus urinaire chez des individus souffrant d'une infection du tissu du tractus urinaire ou prédisposés à celle-ci. Les procédés et les compositions comprennent l'administration de catéchines (et de métabolites urinaires actifs tels que le pyrogallol) et d'agents alcalinisant l'urine (par exemple le bicarbonate de sodium ou le citrate de potassium), seuls ou en combinaison, pour traiter des infections bactériennes urinaires.
PCT/US2022/014429 2021-01-29 2022-01-28 Compositions et procédés de traitement d'infections bactériennes WO2022165263A1 (fr)

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