WO2018019031A1 - Composition pharmaceutique comprenant un ionophore et un antibiotique bêta-lactame et utilisation associée - Google Patents

Composition pharmaceutique comprenant un ionophore et un antibiotique bêta-lactame et utilisation associée Download PDF

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WO2018019031A1
WO2018019031A1 PCT/CN2017/087583 CN2017087583W WO2018019031A1 WO 2018019031 A1 WO2018019031 A1 WO 2018019031A1 CN 2017087583 W CN2017087583 W CN 2017087583W WO 2018019031 A1 WO2018019031 A1 WO 2018019031A1
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ionophore
lactam antibiotic
lasalocid
group
salinomycin
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PCT/CN2017/087583
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Brigitte Gicquel
Wei Huang
Xinwei Wang
Julien BRIFFOTAUX
Mena CIMINO
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Institut Pasteur Of Shanghai, Chinese Academy Of Sciences
Institut Pasteur
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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
    • A61K31/351—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 not condensed with another ring
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to a combination of ionophore and ⁇ -lactam antibiotic and as well as methods of use thereof in treating tuberculosis, especially in inhibiting the development of the tuberculosis disease.
  • Tuberculosis is primarily a disease of the lung and is characterized by chronic coughing, blood-tinged sputum, fever, night sweats, and a loss of appetite.
  • tuberculosis (TB) remains a major public health problem. According to the report of the World Health Organization, about 10 million cases occur each year, among which 480,000 cases are multidrug-resistant tuberculosis (MDR-TB) , accounting for 5%of all cases.
  • XDR Extensively drug-resistant Mycobacterium tuberculosis and MDR-TB found in India are resistant to all anti-tuberculosis drugs.
  • the current World Health Organization approved therapy for treating pulmonary non MDR-TB in adult patients is a four-drug combination of rifampicin, isoniazid, pyrazinamide, and ethambutol for six months. Although this treatment is very effective, drug shortage and lack of effective supervision would affect the efficacy. This requires developing new drug or new drug combination therapy regimen to shorten the course of treatment.
  • the treatment of MDR-TB cases requires administration of 2 nd line drugs for at least 9 to 11 months.
  • the 2 nd line drugs include fluoroquinolones, amikacin, kanamycin, capreomycin and the like, which are toxic and can only cure 60%to 75%cases when using the previously 13 to 26 months recommended W. H. O. regimen.
  • the present invention is to provide a pharmaceutical composition, comprising ionophore, ⁇ -lactam antibiotic and pharmaceutically acceptable carrier.
  • the ionophore is selected from the group consisting of nigericin, A23187, salinomycin, and the combination thereof.
  • the ionophore is nigericin.
  • the ⁇ -lactam antibiotic is selected from the group consisting of meropenem, amoxicillin, tebipenem, and the combination thereof. In another embodiment, the ⁇ -lactam antibiotic is selected from the group consisting of meropenem, amoxicillin, and the combination thereof.
  • the ⁇ -lactam antibiotic is carbapenem antibiotic.
  • the pharmaceutical composition further comprises ⁇ -lactamase inhibitor.
  • the ⁇ -lactamase inhibitor is potassium clavulanate.
  • the weight ratio of the ionophore and ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, most preferably 1: 1.
  • the total content of the ionophore and ⁇ -lactam antibiotic is from 1 to 99%, preferably from 5 to 90%by weight of the pharmaceutical composition.
  • the weight ratio of ionophore, ⁇ -lactam antibiotic and ⁇ -lactamase inhibitor is from 1: 100: 1000 to 100: 1: 10, preferably from 1: 20: 500 to 20: 1: 25, more preferably is 4: 1: 250.
  • the total content of the ionophore, ⁇ -lactam antibiotic and ⁇ -lactamase inhibitor is from 1 to 99%, preferably from 5 to 90%by weight of the pharmaceutical composition.
  • the pharmaceutical composition is for the treatment of tuberculosis and/or for the inhibition of Mycobacterium tuberculosis complex (MTBC) strains multiplication.
  • MTBC Mycobacterium tuberculosis complex
  • the pharmaceutical composition is in an oral dosage form or in an injectable dosage form.
  • the pharmaceutical composition further comprises other pharmaceutically active ingredient, including active ingredient for the treatment of tuberculosis.
  • Another aspect of the present invention is to provide a use of the above pharmaceutical composition in the manufacture of a medicament for the treatment of tuberculosis and/or for inhibition of MTBC strains multiplication in a subject in need thereof.
  • the Mycobacterium tuberculosis is selected from the group consisting of drug-resistant Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis, extensively drug-resistant Mycobacterium tuberculosis and the combination thereof.
  • the inhibition of MTBC strains multiplication includes inhibition of the growth and reproduction of MTBC strains.
  • Another aspect of the present invention is to provide a kit comprising:
  • the kit further comprising:
  • the instruction is further for treating tuberculosis and/or for inhibiting MTBC strains multiplication by the combination of ionophore, ⁇ -lactam antibiotic and ⁇ -lactamase inhibitor.
  • the medicaments in the first, the second and the third compartments are formulations containing the ionophore, ⁇ -lactam antibiotic and ⁇ -lactamase inhibitor, respectively.
  • the medicaments are in an oral dosage form or in an injectable dosage form.
  • the kit is for treatment of tuberculosis and/or for inhibition of MTBC strains multiplication in a subject in need thereof.
  • the ionophore, ⁇ -lactam antibiotic and ⁇ -lactamase inhibitor are administered simultaneously or sequentially.
  • Another aspect of the present invention is to provide a non-therapeutic method for inhibiting MTBC strains multiplication in vitro, comprising the step of incubating MTBC strains in the presence of ionophore, ⁇ -lactam antibiotics and optionally ⁇ -lactamase inhibitors, to inhibit MTBC strains multiplication.
  • the ionophore is administrated at dose of 0.1 to 1 ⁇ g/ml, preferably 0.15 ⁇ g/ml.
  • the ⁇ -lactam antibiotic is administrated at dose of 0.01 to 0.1 ⁇ g/ml, preferably 0.018 ⁇ g/ml.
  • ⁇ -lactamase inhibitor is administrated at dose of 1 to 10 ⁇ g/ml, preferably 2.5 ⁇ g/ml.
  • Another aspect of the present invention is to provide a method for the treatment of tuberculosis and/or for the inhibition of MTBC strains multiplication, comprising the step of:
  • the active ingredients are administrated simultaneously or sequentially.
  • said subject includes both human and non-human mammals.
  • the MTBC strain is Mycobacterium tuberculosis.
  • Figure 1 shows the changes in colony forming units (CFU) per milliliter of culture in presence of different drug or drug combination. Compared with individual administration, combined administration of nigericin and meropenem significantly inhibits the growth of BCG which belongs to the group of MTBC strains.
  • Figure 2 shows the synergistic interactions between A23187 and tebipenem (with 2.5 mg/L clavulanic acid) against intracellular MTBC strains. Drug concentrations are in mg/L.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable.
  • Those in need of the treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those for which the condition or disorder is to be prevented.
  • Tuberculosis is a chronic infectious disease caused by MTBC strains infection.
  • MTBC strains may invade various organs of human body, but the main target is the lung, which is known as pulmonary tuberculosis.
  • the MTBC strains are a genetically related group of Mycobacterium species that can cause tuberculosis in humans or other living organisms.
  • the MTBC strains include Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium orygis, Mycobacterium bovis and the Mycobacterium bovis BCG strains, Mycobacterium microti, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium suricattae, Mycobacterium mungi.
  • Multi-drug-resistant tuberculosis is a form of tuberculosis (TB) infection caused by MTBC strains that are resistant to at least two of the most powerful first-line anti-TB medications, isoniazid and rifampin.
  • Extensively drug-resistant tuberculosis is defined as TB due to MTBC strains that have developed resistance to at least rifampicin and isoniazid, as well as to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, capreomycin, or amikacin.
  • the terms “inhibition of MTBC strains multiplication” and “treatment of tuberculosis” are used interchangeably, including inhibition of the growth and reproduction of MTBC strains and extension of the tuberculosis disease.
  • Ionophore also known as carboxyl polyethers, polyether antibiotics or polyether ionophore, forms electrically neutral complexes with monovalent or divalent cations, catalysing electrically silent exchanges of cations or protons across a variety of biological membranes. These molecules function by rendering cell or intracellular membranes permeable to cations which are normally asymmetrically distributed across biological membranes thereby forming steep concentration gradients.
  • Example of Ionophore includes monensin (also known as A-3823A) , narasin A (also known as A-28086A) , narasin B (also known as A-28086B) , narasin D (also known as A-28086D) , lasalocid, salinomycin, and maduramicin, alborixin (also known as S-14750A, CP-38, 986) , laidlomycin (also known as AB-78) , lenoremycin (also known as A-130A, Ro21-6150) , A-130B, A-130C, dianemycin (also known as A-150, M5-16183) , A-204A, A-204B, Ionomycin (also known as A-218) , deoxylaidlomycin (also known as A-712) , calcimycin (also known as A-23187) , septamycin (also known as BL-580 ⁇ and A-28695
  • the Ionophore is selected from the group comprising salinomycin; lasalocid; narasin; maduramicin; monensin, laidlomycin, and semduramicin. More preferably, the ionophore is selected from the group consisting of nigericin, A23187, salinomycin. More preferably, the ionophore is nigericin and/or A23187.
  • Nigericin is a polycyclic ether carboxylic acid compound. It mainly functions for the exchange between proton and potassium cation. Similar to the formation of complexes between valinomycin and potassium cation, the negatively charged carboxylated nigericin interacts with the cation to form a nigericin-potassium complex for proton-potassium exchange.
  • nigericin may form complexes with metal cations and penetrate the lipid bilayer and the cell membrane of the bacterium, thus changing the ion gradient in and outside the bacteria, increasing penetration into the bacterium, leading to bacterial swelling and forming vacuoles until cell death.
  • nigericin may form complexes with metal cations and penetrate the lipid bilayer and the cell membrane of the bacterium, thus changing the ion gradient in and outside the bacteria, increasing penetration into the bacterium, leading to bacterial swelling and forming vacuoles until cell death.
  • nigericin C 40 H 68 O 11 , with the molecular weight of 724.96. Its structure is shown as follows:
  • A23187 is a mobile ion-carrier that forms stable complexes with divalent cations.
  • A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of Streptomyces chartreusensis.
  • A23187 has antibiotic properties against Gram-positive bacteria and fungi. It also acts as a divalent cation ionophore, allowing these ions to cross cell membranes, which are usually impermeable to them. It is used in laboratories to increase intracellular Ca 2+ levels in intact cells. It also uncouples oxidative phosphorylation, the process cells use to synthesize Adenosine triphosphate for energy. In addition, A23187 inhibits mitochondrial ATPase activity. A23187 also induces apoptosis in some cells (e.g. mouse lymphoma cell line, or S49, and Jurkat cells) and prevents it in others (e.g. cells dependent on interleukin 3 that have had the factor withdrawn) .
  • some cells e.g. mouse lymphoma cell line, or S49, and Jurkat cells
  • A23187 is C 29 H 37 N 3 O 6 , with the molecular weight of 523.62. Its structure is shown as follows:
  • ⁇ -lactam antibiotic refers to a large class of antibiotics with the ⁇ -lactam ring in their chemical structures and is therefore susceptible to degradation by ⁇ -lactamases.
  • Such antibiotics have the advantages of strong bactericidal activity, low toxicity, applicability to broad indications and excellent clinical efficacy.
  • the modification to the chemical structure, especially the side chain of such drugs forms a number of antibiotics with different antibacterial profile and antibacterial effect, as well as a variety of clinical pharmacological properties.
  • ⁇ -lactam is the most widely used antibiotic. It induces cell apoptosis mainly by inhibiting synthesis and metabolism of bacterial peptidoglycan.
  • ⁇ -lactam antibiotics have not been used in the treatment of tuberculosis, except for those multidrug-resistant MTBC infection cases in which existing treatments do not work. The reason for this is mainly due to ⁇ -lactamase BlaC encoded by the MTBC chromosome, as well as low permeability of such drugs in the bacterial cell wall.
  • Non-limiting examples of ⁇ -lactam antibiotic include the most commonly used penicillin and cephalosporins, as well as the recently developed cephamycin, thiomycin, monocyclic ⁇ -lactam and other atypical ⁇ -lactam antibiotics.
  • Non-limiting examples of ⁇ -lactam antibiotic useful with respect to the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams.
  • Non-limiting examples include carbapenems (e.g. meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem/betamipron and biapenem as well as razupenem, tebipenem, lenapenem and tomopenem) , ureidopenicillins (e.g. piperacillin) , carbacephems (e.g. loracarbef) and cephalosporins (e.g. cefpodoxime, ceftazidime, cefotaxime, ceftriaxone, ceftobiprole, and ceftaroline) .
  • carbapenems e.g. meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem/betamipron and biapenem as well as razupenem, tebipenem, lenapenem and tom
  • ⁇ -lactam antibiotic agents include temocillin, piperacillin, cefpodoxime, ceftazidime, cefotaxime, ceftriaxone, meropenem, faropenem, imipenem, loracarbef, ceftobiprole, ceftaroline.
  • Carbapenem antibiotics are atypical ⁇ -lactam antibiotics with the widest antibacterial profile and the strongest antibacterial activity. Their structures are similar with the penicillium ring of penicillin, except for the sulfur atom on the thiazole ring replaced by carbon, and the unsaturated double bond between C2 and C3. In addition, its 6-hydroxyethyl side chain is in a trans-conformation. Their affinity with BlaC is very low and is not affected by the ⁇ -lactamase activity.
  • the preferred ⁇ -lactam antibiotics include meropenem, amoxicillin and tebipenem.
  • meropenem a ⁇ -lactam antibiotic classified as carbapenem
  • carbapenem an injectable antibiotic for the treatment of a variety of different infections, with very broad antibacterial profile.
  • Amoxicillin is one of the most commonly used semi-synthetic penicillin-based broad-spectrum ⁇ -lactam antibiotics. It is present as white powder with a half-life of about 61.3 minutes. It is stable under acidic conditions, with 90%absorbed in gastrointestinal tract. Amoxicillin has a strong anti-bacterial activity, as well as strong ability to penetrate the cell membrane. It is one of the most widely used semi-synthetic oral penicillin, prepared as capsules, tablets, granules, dispersible tablets, and the like, and now often forms dispersible tablets with clavulanic acid.
  • Amoxicillin is C 16 H 19 N 3 O 5 S, with the molecular weight of 365.411. Its structure is shown as follows:
  • Tebipenem is a broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of ⁇ -lactam antibiotics. It binds to bacterial penicillin-binding protein (PBP) , inhibits the synthesis of bacterial cell walls, and is an oral carbapenem antibiotic.
  • PBP penicillin-binding protein
  • tebipenem C 22 H 31 N 3 O 6 S 2 , with the molecular weight of 497.63. Its structure is shown as follows:
  • the agent able to inhibit beta-lactamase includes Clavulanic Acid, Sulbactam, Sultamicillin, Tazobactam, Renal Dipeptidase Inhibitors (Cilastatin) , and Renal Protectant (Betamipron) .
  • Clavulanic acid is an irreversible competitive ⁇ -lactamase inhibitor. It causes enzyme inactivation after binding with the enzyme, and thus exhibits a strong inhibitory activity. Clavulanic acid not only acts on Staphylococcus aureus ⁇ -lactamase, but also inhibits Gram-negative bacillus ⁇ -lactamase. Its combination with penicillins and/or cephalosporins significantly increases the antibacterial activity of beta-lactams and decreases their minimum inhibitory concentration (MIC) . As a result, the drug efficacy is increased up to more than ten times, causing the resistant strains to recover its sensitivity.
  • MIC minimum inhibitory concentration
  • the chemical formula of clavulanic acid is C 8 H 9 NO 5 , with the molecular weight of 199.16. Its structure is shown as follows:
  • the ionophore may be administered prior to, simultaneously with, or subsequent to a ⁇ -lactam antibiotic (“co-administration”) .
  • the ionophore and ⁇ -lactam antibiotic may be administered separately by different routes, if desired.
  • administration or administrating is used to denote simultaneous or sequential administration. Preferably, such administration produces a synergistic effect.
  • administering refers to bringing a subject, tissue, organ or cells in contact with the combination or composition described in this disclosure.
  • the present invention encompasses administering the combination or composition described in this disclosure to a patient or subject.
  • a “subject, ” “patient” and “individual, ” used equivalently herein, refers to a mammal, preferably a human, that either: (1) is developing tuberculosis due to MTBC strains, such disease being remediable, treatable, or diminished in severity by administration of the combination or composition according to the invention; or (2) is susceptible to such an infection that is preventable by administering same.
  • synergy and “synergistic effect” indicate that the effect produced when two or more drugs are co-administered is greater than would be predicted based on the effect produced when the compounds are administered individually.
  • a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds (i.e., sub-therapeutic dosages) .
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • Synergy can result in lower cytotoxicity, increased anti-tuberculosis effect, or some other beneficial effect of the combination compared with the individual components.
  • One embodiment provides a combination, comprising: (a) an ionophore; and (b) a ⁇ -lactam antibiotic.
  • the ionophore is selected from the group as defined above.
  • the ionophore is selected from the group consisting of nigericin, A23187, salinomycin, and the combination thereof.
  • the ⁇ -lactam antibiotic is selected from the group as defined above.
  • the ⁇ -lactam antibiotic is carbapenem or penicillins antibiotic.
  • the ⁇ -lactam antibiotic is selected from the group consisting of meropenem, amoxicillin and tebipenem.
  • the weight ratio of the ionophore and the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the combination further comprises (c) ⁇ -lactamase inhibitor.
  • the ⁇ -lactamase inhibitor is selected from the group as defined above.
  • the ⁇ -lactamase inhibitor is potassium clavulanate.
  • the weight ratio of the ionophore, the ⁇ -lactam antibiotic and the ⁇ -lactamase inhibitor is from 1: 100: 1000 to 100: 1: 10, more preferably 1: 20: 500 to 20: 1: 25, most preferably 4: 1: 250.
  • an ionophore is selected from the group consisting of nigericin, A23187, salinomycin; and (b) a ⁇ -lactam antibiotic selected from the group of carbapenem or penicillins antibiotic.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • an ionophore is selected from the group consisting of nigericin, A23187, salinomycin; and (b) a ⁇ -lactam antibiotic selected from the group of meropenem, amoxicillin and tebipenem.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the weight ratio of the ionophore, the ⁇ -lactam antibiotic and the ⁇ -lactamase inhibitor is from 1: 100: 1000 to 100: 1: 10, more preferably 1: 20: 500 to 20: 1: 25, most preferably 4: 1: 250.
  • Another embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) an ionophore; (b) a ⁇ -lactam antibiotic; and optionally (c) a pharmaceutically acceptable carrier.
  • the ionophore is selected from the group as defined above.
  • the ionophore is selected from the group consisting of nigericin, A23187, salinomycin, and the combination thereof.
  • the ⁇ -lactam antibiotic is selected from the group as defined above.
  • the ⁇ -lactam antibiotic is carbapenem or penicillins antibiotic.
  • the ⁇ -lactam antibiotic is selected from the group consisting of meropenem, amoxicillin, and tebipenem.
  • the weight ratio of the ionophore and the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, most preferably 1: 1.
  • the composition further comprises ⁇ -lactamase inhibitor.
  • the ⁇ -lactamase inhibitor is selected from the group as defined above.
  • the ⁇ -lactamase inhibitor is potassium clavulanate.
  • the weight ratio of the ionophore, the ⁇ -lactam antibiotic and the ⁇ -lactamase inhibitor is from 1: 100: 1000 to 100: 1: 10, preferably 1: 20: 500 to 20: 1: 25, more preferably 4: 1: 250.
  • composition comprising: (a) an ionophore selected from the group consisting of nigericin, A23187, salinomycin; and (b) a ⁇ -lactam antibiotic selected from the group of carbapenem or penicillins antibiotic.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • composition comprising: (a) an ionophore is selected from the group consisting of nigericin, A23187, salinomycin; and (b) a ⁇ -lactam antibiotic selected from the group of meropenem, amoxicillin and tebipenem.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the weight ratio of the ionophore to the ⁇ -lactam antibiotic is from 1: 100 to 100: 1, preferably 1: 20 to 20: 1, more preferably 1: 5 to 5: 1, more preferably 1: 1.
  • the weight ratio of the ionophore, the ⁇ -lactam antibiotic and the ⁇ -lactamase inhibitor is from 1: 100: 1000 to 100: 1: 10, more preferably 1: 20: 500 to 20: 1: 25, most preferably 4: 1: 250.
  • Another embodiment provides use of the combination defined as above or the composition defined as above in the manufacture of medicament for treatment of tuberculosis or for inhibiting MTBC strains multiplication.
  • the MTBC strains are selected from the group consisting of drug-resistant MTBC strains, multidrug-resistant MTBC strains, extensively drug-resistant MTBC strains and the combination thereof.
  • the ionophore, ⁇ -lactam antibiotic and optionally ⁇ -lactamase inhibitor are provided simultaneously, sequentially or separately.
  • Another embodiment provides a method for treating tuberculosis or for inhibiting Mycobacterium tuberculosis complex strains multiplication, comprising administering the combination as defined above or the composition as defined above to a subject in need thereof.
  • the MTBC strains are selected from the group consisting of drug-resistant MTBC strains, multidrug-resistant MTBC strains, extensively drug-resistant MTBC strains and the combination thereof.
  • kits comprising:
  • kit as defined above, further comprising:
  • a third compartment containing ⁇ -lactamase inhibitor or a medicament comprising the ⁇ -lactamase inhibitor.
  • the MTBC strain is Mycobacterium tuberculosis.
  • the present invention provides pharmaceutical composition
  • pharmaceutical composition comprising: (a) ionophore; (b) ⁇ -lactam antibiotics; optionally (c) ⁇ -lactamase inhibitors; and (d) pharmaceutically acceptable carriers.
  • Said carriers include but are not limited to: saline, buffers, glucose, water, glycerol, ethanol, powders, and combinations thereof.
  • the pharmaceutical formulation matches with the administration route.
  • the pharmaceutical compositions of the present invention may be prepared as injections, for example, prepared through conventional methods using physiological saline or aqueous solutions containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules should be prepared under aseptic conditions.
  • the pharmaceutical combination of the present invention may also be formulated as a powder for inhalation.
  • One preferred dosage form is oral formulation.
  • the pharmaceutical compositions of the present invention may also be administered with other therapeutic agents.
  • the present invention further provides a kit for treatment of MTBC strains multiplication, comprising:
  • the weight ratio of ionophore, ⁇ -lactam antibiotic and ⁇ -lactamase inhibitor is from 1: 100: 1000 to 100: 1: 10, preferably from 1: 20: 500 to 20: 1: 25, most preferably 4: 1: 250.
  • the pharmaceutical composition and kit of the present invention is suitable for the treatment of tuberculosis, preferably for the treatment of drug-resistant tuberculosis, more preferably for the treatment of multidrug-resistant tuberculosis.
  • the pharmaceutical composition and kit of the present invention is suitable for the inhibition of MTBC strains multiplication.
  • Said MTBC strains include drug-resistant MTBC strains, multidrug-resistant MTBC strains and extensively drug-resistant MTBC strains.
  • the MTBC strain is Mycobacterium tuberculosis.
  • the formulations of the present invention may be administered three or four times per day, or administered once a day in a sustained release manner. Preferably, the formulation is administered once a day, thereby significantly improving patient compliance.
  • the effective dose of the active ingredient may vary with the severity of the disease to be treated, and the like.
  • the present invention also provides a method of treating tuberculosis using the three active ingredients of the invention or the corresponding medicament.
  • Said method comprises the step of administering to human or non human living organisms an effective amount of: (a) an ionophore; (b) a ⁇ -lactam antibiotic; and optionally (c) a ⁇ -lactamase inhibitor, or comprises the step of administering a pharmaceutical composition comprising (a) , (b) and (c) .
  • the active ingredients of the present invention may be mixed with one or more pharmaceutically acceptable carriers or excipients such as solvents, diluents and the like. They may be administered orally in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions (containing, for example, about 0.05-5%suspending agent) , syrups (containing, for example, about 10-50%sugar) , and elixirs (containing about 20-50%ethanol) . Alternatively, they may also be administered parenterally in the form of a sterile injectable solution or suspension (containing about 0.05-5%suspending agent in the isotonic medium) .
  • such pharmaceutical formulations may contain from about 0.01%to about 99%, more preferably from about 0.1%to about 90%by weight of the active ingredients, which are mixed with the carrier.
  • the active ingredients or the pharmaceutical compositions of the present invention may be administered through conventional route, including, but not limited to, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, oral, or topical administration.
  • Preferred administration routes include oral, intramuscular or intravenous administration.
  • compositions are solid compositions, particularly oral agents.
  • compositions of the present invention are able to inhibit the growth of MTBC strains, exhibits significant synergistic effect, and have the potential to be used in the treatment of multidrug-resistant tuberculosis.
  • the above components are dissolved in 100 ml distilled water, and are filter sterilized through 0.2 ⁇ m membrane.
  • the above components are dissolved in 100 ml distilled water, and are filter sterilized through 0.2 ⁇ m membrane.
  • the time-kill method is to compare the amount of cultivable bacteria in the culture after each component is administered to the bacteria individually or in combination.
  • the criteria for the evaluation are that, compared to the individual administration at the same concentration, the number of cultivable bacteria after combined administration exhibits a 2 log10 decrease, it is determined that, synergistic effect is achieved with the combined administration.
  • Chequerboard titration test method is to use the method of checkerboard titration in the microplate to determine the minimum inhibitory concentration of each component when administered in combination.
  • FICA+ FICB the FICI index of the combination was determined by adding the two FIC index of the individual drugs (FICA+ FICB) .
  • M. marinum (ATCC BAA-535) is a human patient isolate from Moffett Hospital, University of California, San Francisco in 1992. Multi-locus sequence typing shows that this strain belongs to sequence type 22 (Yip MJ et al. Evolution of Mycobacterium ulcerans and other mycolactone-producing mycobacteria from a common Mycobacterium marinum progenitor. J. Bacteriol. 2007; 189: 2021–2029) .
  • M. smegmatis strain is the M. smegmatis mc2 155 strain described in “Isolation and characterization of efficient plasmid transformation mutants of Mycobacterium smegmatis ” by Snapper SB, Melton RE, Mustafa S, Kieser T, Jacobs WR Jr. Mol Microbiol. 1990 Nov; 4 (11) : 1911-9.
  • M. aurum is the stain ATCC 23366 kept in the collection of Institut Pasteur under the number CIP104465T. It is described in Int. J. Syst. Bacteriol., 1980 30 : 325 and J. Gen. Microbiol., 1966 45 : 253.
  • M. avium is from the ATCC collection ATCC 25291.
  • M. tuberculosis H37Rv is from the ATCC collection (ATCC 27294) .
  • BCG Mycobacterium bovis BCG
  • BCG is a vaccine for the prevention of tuberculosis and is prepared using viable Mycobacterium bovis BCG that are non-pathogenic for non immune-compromised living organisms.
  • BCG is a member of the group of MTBC strains, and the inventors have found the synergistic effects of ionophore and ⁇ -lactam antibiotics in BCG. This will help to further develop a new anti-bacterial drug combination. Such combination can also be used for the treatment of multidrug-resistant tuberculosis and to enhance the function of ⁇ -lactam in its existing antibacterial profile.
  • bovis BCG strain 1173 P2 is described in “The stability and immunogenicity of a dispersed-grown freeze-dried Pasteur BCG vaccine” by Gheorghiu M, Lagrange PH, Fillastre C. J Biol Stand. 1988 Jan; 16 (1) : 15-26.
  • M. bovis BCG was cultured in 7H9 OADC media (Beckton Dickinson) and kept frozen at -20°C in tubes after addition of 50%glycerol (final concentration) for conservation (the cryopreserved BCG) .
  • cryopreserved BCG was thawed and inoculated into 7H9 broth, incubated at 37°C, 220 rpm until OD600 achieved 0.6-0.8.
  • the above cultures were inoculated at a ratio of 1: 100 into 7H9 broth containing 0.31 ⁇ g/ml of nigerincin or 0.31 ⁇ g/ml of meropenem, respectively. It was also inoculated into a 7H9 broth containing 0.31 ⁇ g/ml of nigerincin and 0.31 ⁇ g/ml of meropenem in the same proportion. An antibiotic-free 7H9 broth was used as a control.
  • nigerincin and meropenem were formulated in a weight ratio of 1: 1 (i.e. molar ratio of 1: 1.89) .
  • the cryopreserved BCG was thawed and inoculated into 7H9 broth.
  • the nigerincin was serially diluted from column to column, and the concentration was from 50 ⁇ g/ml to 0.39 ⁇ g/ml.
  • the amoxicillin was serially diluted from row to row, and the concentration is from 2.5 ⁇ g/ml to 0.009 ⁇ g/ml.
  • the potassium clavulanate was added until a final concentration of 2.5 ⁇ g/ml. The final volume for each well was 100 ⁇ l.
  • the samples were added in an 8x8 manner.
  • the anti-BCG FICI value of the above combination (nigericin + amoxicillin + potassium clavulanate) was 0.5.
  • FICI ⁇ 0.5 is a criteria of the synergistic effect between a combination.
  • the combination of nigericin, amoxicillin and potassium clavulanate brought synergistic effect.
  • nigerincin 0.15 ⁇ g/ml
  • amoxicillin 0.018 ⁇ g/ml
  • potassium clavulanate 2.5 ⁇ g/ml (i.e. the molar concentration ratio of nigerincin : amoxicillin : potassium clavulanate is 4: 1: 250) .
  • Antibiotic solutions were prepared at a concentration of 1 mg/ml in distilled water, filter sterilized, and frozen until use. All compounds to be screened were dissolved in 100%dimethylsulfoxide (DMSO) and stored as frozen stocks at a concentration of 2 mg/ml. Resazurin sodium powder was prepared at 0.01% (w/v) in distilled water, filter sterilized, and stored at 4°C for up to one week. All chemicals were obtained from Sigma-Aldrich, USA.
  • DMSO dimethylsulfoxide
  • M. marinum, M. abscessus, M. avium, and M. bovis BCG and M. tuberculosis H37Rv were cultured in Middlebrook 7H9 broth containing 10% (v/v) ADC enrichment (albumin, dextrose, catalase; Becton Dickinson) and 0.05%Tween 80, or Middlebrook 7H11 agar medium containing 10% (v/v) OADC enrichment (oleic acid, albumin, dextrose, catalase; Becton Dickinson) .
  • M. aurum and M. smegmatis were grown in LB broth containing 0.05%Tween 80, or LB agar containing Difco agar (1.5%) . All mycobacteria were cultured at 37°C except for M. marinum that was cultured at 30°C.
  • the compounds tested during this study were purchased from Topscience Co., Ltd, China. They were screened in search of their activity against whole-cells of M. aurum as determined using the resazurin-reduction assay.
  • a fresh culture of M. aurum in exponential phase in LB broth (OD 600 ⁇ 0.6-0.8) was diluted to OD 600 ⁇ 0.2-0.3 in the same culture medium.
  • a mixture of 50 ⁇ L fresh LB broth, 2.5 ⁇ L of the diluted M. aurum suspension, and 15 ⁇ L resazurin solution was added to each of 384-well plates (Thermo Scientific) .
  • the M. aurum inoculum was replaced by 2.5 ⁇ L LB medium as a sterility control.
  • Drug interactions between the ionophore and other anti-mycobacterial drugs were performed with M. tuberculosis cultures, using resazurin as a viability marker in the chequerboard titration assay (Chen P, Gearhart J, Protopopova Met al. Synergistic interactions of SQ109, a new ethylene diamine, with front-lineantitubercular drugs in vitro. J Antimicrob Chemother 2006; 58: 332-7. ) .
  • Macrophages were infected M. tuberculosis H37Rv at a multiplicity of infection of 0.5 bacteria/cell.
  • the infected cells were washed and incubated in fresh medium with or without drugs after 2 hours of infection. After an additional 6 days culture, cells were lysed by resuspension in 0.1%Triton X-100 in distilled water and bacteria enumeration were done after 3 weeks at 37°C (Tailleux L, Neyrolles O, Honore-Bouakline S, et al. Constrained intracellular survival of Mycobacterium tuberculosis in human dendritic cells, J Immunol, 2003, vol. 170: 1939-48) .
  • M. Tuberculosis and two other pathogenic mycobacterial species M. abscessus and M. avium.
  • M. tuberculosis was fully susceptible to nigericin and A23187 whereas M. abscessus and M. avium appeared to be naturally resistant to all three compounds.
  • Salinomycin showed higher MIC with M. tuberculosis and was not retained for further studies.
  • M. aurum was the most sensitive to the three ionophores.
  • a The concentration of clavulanic acid was 2.5 ⁇ g/ml.
  • A23187 enhance the activity of beta-lactam against intracellular M. tuberculosis at nontoxic concentrations
  • Nigericin and salinomycin are lipophilic compounds that can form complexes with the metal cations and, to a lesser extent, K + and Na + occurring with H + exchange due to the proton motive force, modifying ion homeostasis.
  • A23187 (calcimycin) is specific for divalent cations, such as Mn 2+ and Ca 2+ . Nigericin and A23187 showed significant antimicrobial activity against M. aurum, M. smegmatis, M. marinum and the pathogenic slow-growing M. tuberculosis complex strains.
  • A23187 enhance the activity of beta-lactam against intracellular bacteria at concentrations that are not toxic for the macrophages.
  • Another investigation showed that adding calcium ionophore A23187 to M. tuberculosis infected macrophage could increase calcium flux into the cells which is thought to block necrosis, stabilize mitochondrial permeability transition (MPT) , decrease mitochondrial cytochrome release, lower caspase activation, and accompany effective anti-mycobacterial activity. Therefore, A23187 could be an adjunct for beta-lactam against M. tuberculosis.
  • Nigericin and A23187 exhibited synergistic interactions with some beta-lactams. This opens the way to use these antibiotics combined with clavulanic acid or other inhibitors of beta-lactamase, cephalosporinase, or carbapenemase activity, together with ionophores, such as A23187, for the treatment of MDR-TB and other infectious bacterial diseases by oral administration.

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Abstract

L'invention concerne une combinaison comprenant un ionophore et un antibiotique β-lactame, ainsi que des méthodes d'utilisation de cette combinaison dans l'inhibition de la multiplication de souches complexes de Mycobacterium tuberculosis ou dans le traitement de la tuberculose.
PCT/CN2017/087583 2016-07-27 2017-06-08 Composition pharmaceutique comprenant un ionophore et un antibiotique bêta-lactame et utilisation associée WO2018019031A1 (fr)

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WO2020151671A1 (fr) * 2019-01-23 2020-07-30 Glycolysis Biomed Co., Ltd Composés de bêta-lactame ou leurs sels destinés à être utilisés dans la prévention ou le traitement à action prolongée d'un trouble du métabolisme du glucose

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WO2013103780A1 (fr) * 2012-01-06 2013-07-11 Trustees Of Boston University Compositions et procédés pour amplifier la production endogène d'espèces réactives de l'oxygène (ros) à partir de bactéries
WO2014121343A1 (fr) * 2013-02-08 2014-08-14 Luoda Pharma Pty Limited Procédés de traitement d'infections microbiennes, y compris la mammite

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Publication number Priority date Publication date Assignee Title
WO2013103780A1 (fr) * 2012-01-06 2013-07-11 Trustees Of Boston University Compositions et procédés pour amplifier la production endogène d'espèces réactives de l'oxygène (ros) à partir de bactéries
WO2014121343A1 (fr) * 2013-02-08 2014-08-14 Luoda Pharma Pty Limited Procédés de traitement d'infections microbiennes, y compris la mammite

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020151671A1 (fr) * 2019-01-23 2020-07-30 Glycolysis Biomed Co., Ltd Composés de bêta-lactame ou leurs sels destinés à être utilisés dans la prévention ou le traitement à action prolongée d'un trouble du métabolisme du glucose

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