WO2022180380A1 - Combinaison de mupirocine avec des photosensibilisateurs à base de porphyrine pour réduire l'émergence d'une résistance aux antibiotiques - Google Patents

Combinaison de mupirocine avec des photosensibilisateurs à base de porphyrine pour réduire l'émergence d'une résistance aux antibiotiques Download PDF

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WO2022180380A1
WO2022180380A1 PCT/GB2022/050477 GB2022050477W WO2022180380A1 WO 2022180380 A1 WO2022180380 A1 WO 2022180380A1 GB 2022050477 W GB2022050477 W GB 2022050477W WO 2022180380 A1 WO2022180380 A1 WO 2022180380A1
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combination
formula
mupirocin
antibacterial agent
compound
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PCT/GB2022/050477
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English (en)
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William G. Love
William Rhys-Williams
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Destiny Pharma Plc
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Priority to CN202280015623.9A priority Critical patent/CN116916911A/zh
Publication of WO2022180380A1 publication Critical patent/WO2022180380A1/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
    • A61K31/351—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
    • A61K31/409—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 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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

Definitions

  • This invention relates to the new use of porphyrin compounds in suppressing the emergence of antibiotic resistance in bacteria.
  • the invention particularly relates to the application of this use in medicine (as well as veterinary and domestic settings) where the prevalence of antibiotic resistance presents a significant threat to life.
  • Background Bacterial infections in humans are relatively common and can range in severity from mild to life-threatening. A bacterial infection can take many different forms depending on its location, type, even the age of the affected individual. Most bacterial skin infections are caused by Staphylococcus aureus or Streptococcus pyogenes.
  • Staphylococcus aureus is also a common cause of human bacterial infections in other parts of the body, including soft tissues, bones, bloodstream, and respiratory tract. Particular conditions that are associated with sXch bacteria include peritonitis, an infection of the inner lining of the abdomen, and impetigo.
  • the treatment of choice for S. aureus infection is penicillin, however the history of S. aureus treatment is marked by the development of resistance to each new class of antistaphylococcal antimicrobial drugs, including the penicillins, sulfonamides, tetracyclines, glycopeptides, and others, complicating therapy.
  • MRSA methicillin-resistant Staphylococcus aureus
  • S. aureus Approximately 20%–30% of healthy adults are persistent carriers, about 50% are transient carriers, and 20% have never been colonised by S. aureus. Colonisation with S. aureus is a major risk factor for staphylococcal infections. It is estimated that approximately 80% of staphylococcal sepsis is of an endogenous origin. Nasal carriage, hair follicle infection (furuncle), or ongoing bone inflammation may appear as the source of sepsis. Staphylococcal infections may also result from direct or indirect contact with a carrier (exogenous infection) (see Kwiatkowski P. et al. , Molecules 2019, 24, 3105). Many global organizations have produced guidelines regarding decolonisation procedures.
  • Kwiatkowski, P. et al. (2019) Microbial Drug Resistance, 25(10), pp.1424-1429 describes the effect of subinhibitory concentrations of trans-Anethole (tA) on antibacterial properties of mupirocin against mupirocin-resistant Staphylococcus aureus strains. The authors showed that tA was able to increase the susceptibility to mupirocin in those strains. However, there is no suggestion that tA can retard or suppress the emergence of mupirocin resistance.
  • tA trans-Anethole
  • EOCs essential oil compounds
  • a first antibacterial agent which is a compound of formula (I) or formula (II), R 4 (R 3 )(R 2 )HN R 1 O NH N O R1 N(R2)(R3)R4 I) II) wher R 1 is a C 1 to C 6 alkylene group; R 2 , R 3 and R 4 are independently C1 to C4 alkyl; and M is a metallic element or a metalloid element, to suppress the emergence of antibiotic resistance in bacteria exposed to a second antibacterial agent.
  • a method of suppressing the emergence of antibacterial resistance in bacteria exposed to a second antibacterial agent which method comprises exposing the bacteria to a first antibacterial agent which is a compound of formula (I) or formula (II) as defined herein.
  • the use and method of the first aspect of the invention may be referred to herein as “the method of the invention”. Mutational antibiotic resistance in a bacterial population typically emerges when that population is exposed to an antibiotic and is able to survive and reproduce. If the characteristics which enabled a bacterium to survive exposure to an antibiotic are passed on to its progeny, the resulting bacterial population is likely to show an increased resistance to that antibiotic.
  • the methods of the invention suppress the emergence of antibiotic resistance in bacteria.
  • the term “suppress” (and related terms, such as “retard”, “reduce” or “inhibit”) we mean that the rate at which mutational antibiotic resistance emerges is reduced (or slowed) relative to the rate at which antibiotic resistance would emerge in the absence of the compound of formula (I) or formula (II) but otherwise under the same conditions.
  • the antibacterial efficacy of a substance for a given bacterial strain may be evaluated through determining the minimum inhibitory concentration (MIC) of that substance for that strain. An increase in the resistance is evidence when the MIC of the substance increases for a bacterial strain over time.
  • the methods of the invention have now been shown to slow (or retard) the rate of increase of the MIC for mupirocin under laboratory conditions when bacteria were repeatedly exposed to a combination of compound of formula (I) or (II) and mupirocin. It is believed that, by exposing bacteria to a combination of compound of formula (I) or (II) and a second antibiotic (e.g. mupirocin), the emergence of mutational resistance to the second antibiotic will be at least partially inhibited, and this will be useful in clinical and veterinary settings.
  • the term “emergence” in the context of resistance refers to the increase in the MIC from an initial lower value to a higher value.
  • a bacterial strain may be classified as resistant or susceptible to a given antibacterial agent depending on whether the MIC for that strain lies above or below an established threshold.
  • a bacterial strain is typically said to be susceptible to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic success, and a bacterial strain is typically said to be resistant to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic failure.
  • resistance of a bacterial strain to an antibacterial agent may be considered to have emerged based on whether the efficacy of the agent has dropped below a given threshold, e.g. if the MIC has increased above a given threshold.
  • the method or use slows the rate at which the MIC the antibacterial agent increases.
  • compounds of formula (I) and (II) may suppress the emergence of antibiotic resistance in bacteria exposed to another antibacterial agent has utility in the treatment or prevention of bacterial infections, particularly in clinical settings.
  • a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent for use in the treatment or prevention of a bacterial infection, wherein the use of the combination suppresses the emergence of antibiotic resistance.
  • a method of treating or preventing a bacterial infection comprises administration of a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent to a subject in need of such therapy (i.e. a subject suffering from said bacterial infection or at risk of suffering from said bacterial infection) to suppress the emergence of antibiotic resistance.
  • a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent in the manufacture of a medicament for treating or preventing a bacterial infection, wherein the use of the combination suppresses the emergence of mutational antibiotic resistance.
  • the combination for use, method and use of the second aspect of the invention may also be referred to herein as “the method of the invention”, together with the first aspect of the invention.
  • the methods of the invention involve the exposure of bacteria to a compound of formula (I) or formula (II) as defined in the first aspect.
  • Compounds of formula (I) or formula (II) may be referred to herein as “compounds of the invention”.
  • the terms C 1-q alkyl, and C 1-q alkylene, groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain.
  • Particular groups which may be represented by R 1 include linear C 1 to C 6 alkylene group, preferably selected from the group consisting of methylene, ethylene, n-propylene and n- butylene. In a particularly preferred embodiment, R 1 is n-propylene.
  • R 2 , R 3 and R 4 may be the same or different. In preferred embodiments, R 2 , R 3 and R 4 are the same.
  • Particular groups which may be represented by R 2 , R 3 and R 4 independently include linear C 1 to C 4 alkyl groups, preferably selected from the group consisting of methyl, ethyl and n-propyl.
  • R 2 , R 3 and R 4 are all the same and represent either ethyl or, particularly, methyl.
  • Compounds of formula (I) and (II) each contain two -O-R 1 -N + -(R 2 )(R 3 )R 4 moieties. Said moieties are bound to the central porphyrin core via separate phenyl rings.
  • a -O-R 1 -N + - (R 2 )(R 3 )R 4 moiety may be attached via any carbon atom on the requisite phenyl ring. Preferably the moiety is attached at one of the 3-, 4- or 5-positions (i.e.
  • each -O-R 1 -N + -(R 2 )(R 3 )R 4 moiety is bound to the relevant phenyl ring in the para position relative to the point of attachment to the porphyrin.
  • the compounds of the invention carry a net positive charge, for example a charge of +2, due to the presence of the two -O-R 1 -N + -(R 2 )(R 3 )R 4 moieties. It will be appreciated by persons skilled in the art that compounds of formulae (I) and (II) may be counterbalanced by counter-anions.
  • Exemplary counter-anions include, but are not limited to, halides (e. g. fluoride, chloride and bromide), sulfates (e.g. decylsulfate), nitrates, perchlorates, sulfonates (e. g. methane sulfonate) and trifluoroacetate.
  • halides e. g. fluoride, chloride and bromide
  • sulfates e.g. decylsulfate
  • nitrates e.g. perchlorates
  • sulfonates e. g. methane sulfonate
  • trifluoroacetate e.g. methane sulfonate
  • Salts which may be mentioned include: acid addition salts, for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. It will be further appreciated by skilled persons that the compounds of formula (I) and (II) may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
  • the term "metallic element” is intended to include a divalent or trivalent metallic element. Preferably, the metallic element is diamagnetic.
  • the metallic element is selected from Zn (II), Cu (II), La (III), Lu (III), Y (III), In (III) Cd (II), Mg (II), Al(III), Ru(II), Ni(II), Mn(III), Fe(III) and Pd (II).
  • the metallic element is Ni(II), Mn(III), Fe(III) or Pd(II).
  • a particular trivalent metallic element that may be mentioned is Fe(III).
  • the term "metalloid" is intended to include an element having physical and chemical properties, such as the ability to conduct electricity, that are intermediate to those of both metals and non-metals.
  • metallic element includes silicon (Si) and germanium (Ge) atoms which are optionally substituted with one or more ligands. It will be appreciated that the terms metallic element and metalloid element include a metal element or a metalloid element having a positive oxidation state, all of which may be substituted by one or more ligands selected from fluoro, OH, OR X wherein R X is C 1 to C 4 alkyl.
  • Preferred compounds of formula (I) that may be used in the first and second aspects of the invention include the following: (a) 5,15-bis-[4-(3-Triethylammonio-propyloxy)-phenyl]-porphyrin dichloride; + NH N + Preferably, this compound is provided as a dichloride salt. (b) 5,15-bis-[3-(3-Trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride; NH N + Preferably, this compound is provided as a dichloride salt.
  • the compound of formula (I) or (II) is 5,15-bis-[4-(3-trimethylammonio- propyloxy)-phenyl]-porphyrin dichloride, 5,15-bis-[3-(3-trimethylammonio-propyloxy)- phenyl]-porphyrin dichloride or 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- iron(III)-porphyrinium trichloride.
  • Compounds of formula (I) and (II) may be synthesised according to methods known in the art, e.g.
  • the second antibacterial agent may be a compound of formula (I) or (II) that is different from the first antibacterial agent.
  • the second antibacterial agent is not a compound of formula (I) or (II).
  • the term “antibacterial agent” as used herein refers to a substance which is capable of inhibiting bacterial growth and/or reproduction, or which is capable of killing bacteria following contact with the organism in vivo or in vitro.
  • the term “antibiotic” typically refers to an agent that either kills or inhibits the growth of a microorganism, the terms “antibacterial” and “antibiotic” may be used interchangeably in the context of the present invention, which principally relates to bacteria.
  • the methods of the invention involve exposing bacteria to an antibacterial agent, e.g.
  • the antibacterial agent e.g. the “second” antibacterial agent
  • the second antibacterial agent is an antibiotic that is useful for treating a skin infection.
  • the form of resistance for which emergence is suppressed by the methods of the invention may be resistance to one of the antibacterial agents (particularly the second antibacterial agent) to which the bacteria are exposed.
  • the emergence of resistance to other antibacterial agents may also be suppressed, e.g. agents that are structurally or functionally similar to the antibacterial agent to which the bacteria are exposed.
  • the methods of the invention may be particularly effective in suppressing the emergence of mutational resistance to topical antibiotics, such as antibiotics that are useful for treating skin infections.
  • topical antibiotics such as antibiotics that are useful for treating skin infections.
  • the methods of this invention are particularly suited to use with topical therapies as it is easier to ensure that the compound of formula (I) or (II) is delivered to the site of the infection at the same time that the bacteria are exposed to the second antibacterial agent.
  • Particular topical antibiotics that may be mentioned in this respect include rumblemulin, fusidic acid and, preferably, mupirocin.
  • the methods of the invention suppress resistance to one or more isoleucine-tRNA synthetase inhibitors, particularly mupirocin.
  • mupirocin resistance Different forms of mupirocin resistance are known, and they may be distinguished according to their genetic nature. High-level mupirocin resistance is usually associated with the presence of the mupA gene, which encodes an alternative IleS enzyme [Hurdle JG, O'Neill AJ, Ingham E, Fishwick C, Chopra I. 2004. Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modelling techniques. Antimicrob. Agents Chemother.48:4366-4376].
  • Low-level mupirocin has also been described and is usually due to the selection of specific mutation(s) within the intrinsic ileS gene (Hurdle et al. ibid.; Antonio M, McFerran N, Pallen MJ.2002. Mutations affecting the Rossman fold of isoleucyl-tRNA synthetase are correlated with low-level mupirocin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 46:438-442).
  • the antibiotic resistance is low-level resistance to mupirocin.
  • the invention is particularly suited to suppressing resistance emergence in those bacteria.
  • the bacteria are selected from, but not limited to, the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus spp..
  • the methods of the invention are particularly suited to suppressing resistance emergence in mupirocin-susceptible bacteria that are also susceptible to XF-73 and/or similar porphyrin-containing compounds.
  • the bacteria are selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus spp.
  • Particular bacteria that may be mentioned in the context of the methods of the present invention are Staphylococcus sp. and Streptococcus sp., particularly Staphylococcus aureus and Streptococcus pyogenes.
  • the methods of the invention are particularly suitable for suppressing resistance emergence in bacteria which have already developed resistance to conventional antibiotic treatments. By this, we mean that the methods are particularly suitable for suppressing resistance emergence in bacteria that are resistant to one or more other antibiotics, i.e.
  • the bacteria in which resistance emergence is suppressed are exposed to at least two antibacterial agents.
  • exposed in this context, we mean that the bacteria are brought into physical contact with said antibacterial agent. The precise method by which physical contact is achieved may depend upon the location of the bacteria.
  • the bacteria may be located within the dermis. Exposure may be achieved by application of the antibacterial agent to the surface of the skin above the site of the infection, so that the agent may then penetrate the epidermis and thereby reach the bacteria.
  • the methods of the invention may be useful in suppressing the emergence of resistance arising during the treatment or prevention of an infection in a subject or a patient.
  • references to “patients” will refer to a living subject being treated, including mammalian (in particular, human) patients, and as such “patients” may also be referred to as “subjects”, and vice versa.
  • references to “patients” also should be considered to refer to individuals displaying no symptoms of the relevant condition, for whom methods of the invention may be used as a preventative or prophylactic measure (as defined herein).
  • references to “patients” may also include references to animals, such as non-mammalian animals (e.g. birds) and, particularly, mammalian animals (e.g. cats, dogs, rabbits, rodents, horses, sheep, pigs, goats, cows, primates, and the like).
  • the methods of the invention may be used in either a clinical or veterinary setting.
  • the methods of the invention may involve administration of the compound of formula (I) or formula (II) to a subject (e.g. a human patient) suffering from a topical bacterial infection, e.g. as part of a method of treating that infection.
  • a subject e.g. a human patient
  • a subject is considering to be suffering from a topical bacterial infection when the presence of the bacteria is causing damage to body tissues. This is usually associated with acute inflammation at the site of infection.
  • the methods of the invention are also useful in preventative measures, particular where a subject does not appear to have an infection, but has an increased susceptibility to the acquisition of an infection, e.g. as a result of colonisation.
  • Staphylococcus aureus For example, around one third of the general population is thought to be colonised with Staphylococcus aureus, with the pooled prevalence of MRSA colonisation being around 1.3% [Salgado CD, et al. Clin. Infect. Dis.2003;36:131–9].
  • the most common site of Staphylococcus aureus colonisation is the anterior nares, though such bacteria are also commonly present in the throat, axilla, rectum, groin, and perineum.
  • the potential for antibiotic resistance to emerge is therefore high in subjects that are undergoing antibiotic therapy.
  • the methods of the invention may be useful in preventing a subject (e.g.
  • references herein to a subject that is “at risk” of suffering from a bacterial infection include references to a subject that is colonised but not infected with said bacteria.
  • the subject may be colonised with or infected with any of the bacteria described herein.
  • the bacteria are Staphylococcus sp. or Streptococcus sp., particularly Staphylococcus aureus or Streptococcus pyogenes
  • the methods of the invention may therefore be used to suppress the emergence of antibiotic resistance in both therapeutic and preventative contexts, i.e. as part of either the treatment or prevention of a bacterial infection.
  • the compound of formula (I) or formula (II) may be administered to a subject suffering from a bacterial infection or colonised with bacteria.
  • the compound of formula (I) or formula (II) and the second antibacterial agent are administered to a subject suffering from a bacterial infection or colonised with bacteria, and they may be administered separately or simultaneously.
  • references herein to the “treatment” of a particular condition or, similarly, to “treating” that condition) take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
  • references herein to “prevention” of a particular condition take their normal meanings in the art.
  • these terms may refer to achieving a reduction in the likelihood of developing the relevant condition or symptoms associated with the relevant condition (for example, a reduction of at least 10% when compared to the baseline level, such as a reduction of at least 20% or, more particularly, a reduction of at least 30%).
  • the term “preventing” may also be referred to as “prophylaxis” of the relevant condition, and vice versa.
  • the emergence of resistance may be detected and quantified through measuring the minimum inhibitory concentration (MIC) and observing an increase therein.
  • MIC minimum inhibitory concentration
  • the MIC for an antimicrobial agent against a specific microorganism is defined as the minimum concentration of an antibacterial agent at which no apparent visible growth of the organism is observed (FDA definition of Minimum Inhibitory Concentration). MICs are typically determined using concentrations derived traditionally from serial twofold dilutions (M07Ed11. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: eleventh edition. Clinical and Laboratory Standards Institute). If resistance emergence in a microorganism is suppressed, the MIC for a given antibacterial agent (i.e. the second antibacterial agent) against the microorganism may remain unchanged or may increase by an amount that is less than would otherwise occur.
  • the increase over a given period of time will be considered to be reduced if it is lower (e.g. reduced by 20%, such as reduced by 50%) in comparison to the increase in MIC for the second antibacterial agent that occurs in the absence of the compound of formula (I) or formula (II) over a similar period of time.
  • the methods of the invention may be particularly suitable for use with subjects that have an increased risk of suffering from a bacterial infection.
  • a subject may be considered to have an increased risk of suffering from a bacterial infection if that subject is due to undergo a surgical or cosmetic procedure.
  • Particular subjects that may be mentioned in this respect include subjects that are due to undergo a surgical or cosmetic procedure and that are colonised with pathogenic bacteria, such as Staphylococcus sp.
  • the compound of formula (I) or formula (II) is administered to a subject has an increased risk of suffering from a bacterial infection, e.g. an infection by Staphylococcus sp. or Streptococcus sp.
  • the methods of the invention may be advantageously used in surgical or cosmetic procedures which involve penetration of the skin or the treatment of a wound or burn. Such procedures would be known to the skilled person and include procedures requiring the use of a catheter, suture or surgical drain. Certain clinical procedures involve the penetration of the skin using a catheter in order to transfer fluid into and out of the body.
  • peritoneal dialysis which involves the insertion of a catheter through the abdominal wall for fluid exchange within the abdomen.
  • the catheter may remain in place for an extended period, typically several months, and the risk of an infection arising from the presence of the catheter is significant.
  • Infections that most commonly arise in subjects receiving peritoneal dialysis include exit site infections, i.e. infections in the skin region around the catheter, and infections in the abdominal cavity which may cause peritonitis, i.e. inflammation of the peritoneum.
  • the methods of the invention may therefore be particularly useful in the prevention of an exit site infection or peritonitis resulting from peritoneal dialysis.
  • the methods may also be useful in the context of wound healing, e.g.
  • the methods of the invention may therefore be particularly useful in the prevention of post-operative wound infections and in treating burn wounds, particularly staphylococcal infections.
  • Cosmetic procedures which may be mentioned in this respect include body piercings, particularly nose piercings, and procedures involving the insertion, adjustment or removal of a cosmetic implant.
  • Bacteria, such as Staphylococcus aureus, that colonise nasal passages can also provide a source of infection for patients. Therefore, patients that undergo surgery may benefit from prior bacterial nasal decolonisation as this will reduce the likelihood of an infection arising that will require medical intervention.
  • Decolonisation may be performed using any method known to a medical professional, e.g. using a nasal ointment, with the aim of significantly reducing the numbers of bacteria resident in or on the body (particularly in the nasal passages).
  • Decolonisation is commonly recommended when a patient is known or suspected to be colonised with a strain of antibiotic-resistant bacteria, such as methicillin- resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin- resistant Staphylococcus aureus
  • Decolonisation may also be recommended when a patient has an increased risk of infection due to another medical condition, such as cancer, diabetes or a condition that weakens the immune system.
  • Decolonisation using the method of the invention may not only significantly reduce the quantity of bacteria present but also reduce the likelihood of bacteria acquiring further antibiotic resistance and remaining in or on the patient.
  • the method of the invention involves nasal decolonisation of Staphylococcus sp.
  • the nasal decolonisation is achieved through the simultaneous administration of the compound of formula (I) or formula (II) and the second antibacterial agent to the patient.
  • Decolonisation particularly nasal decolonisation, may be performed for patients regardless of whether they are due to undergo a surgical procedure.
  • Decolonisation may be desired as part of a wider decolonisation program to reduce the prevalence of bacterial infections, particularly antibiotic-resistant infections such as MRSA, in patients or to reduce the spread of such strains in medical practices (particularly hospitals), care homes, veterinary surgeries.
  • the invention relates to a method of preventing a bacterial infection which method comprises administration of a combination comprising a compound of formula (I) or formula (II) as defined herein and a second antibacterial agent to a subject colonised with bacteria (e.g. MRSA) to decolonise the subject.
  • Mupirocin is commonly used for bacterial decolonisation, particularly MRSA decolonisation.
  • mupirocin-containing products include Bactroban® Nasal Ointment which contains mupirocin calcium at a concentration equivalent to 2% w/w mupirocin free acid ointment. This is a paraffin-based nasal ointment containing a glycerin ester (typically bis-diglyceryl polyacyladipate-2).
  • Other mupirocin-containing products include Bactroban® Ointment which is indicated for the topical treatment of impetigo due to Staphylococcus aureus and Streptococcus pyogenes, and Bactroban® Cream which is indicated for the treatment of secondarily infected traumatic skin lesions.
  • antibiotics which may be used include fusidic acid and rumblemulin.
  • examples of such products include Fucidin (fusidic acid) which is a 20 mg/g cream, and Altabac (rumblemulin) which is a 1% ointment.
  • Antibiotic formulations known to the person skilled in the art, including the mupirocin, fusidic acid and rumblemulin formulations disclosed here, may be used in the methods of the invention, e.g. as a source of the (second) antibacterial agent.
  • the compounds of formula (I) and (II) and the second antibacterial agent will generally be administered in the form of one or more pharmaceutical formulations in admixture with a pharmaceutically acceptable excipient, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable excipient may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable excipients may also impart an immediate (e.g. rapid), or a modified (e.g. delayed), release of the active ingredients.
  • Suitable pharmaceutical formulations may be commercially available or otherwise be described in the literature (see, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995) and Martindale – The Complete Drug Reference (35 th Edition), and the documents referred to therein), the relevant disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques. Suitable pharmaceutical formulations for use with the compounds of the invention are also described in International patent application no. WO 2006/000765. For example, for application topically, e.g. to the skin or a wound site, the compounds (e.g.
  • the compound of formula (I) or (II) and the second antibacterial agent) can be administered (separately or together) in the form of a lotion, solution, cream, gel, ointment or dusting powder (for example, see Remington, supra, pages 1586 to 1597).
  • the compounds can be formulated as a suitable ointment containing the active compound(s) suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream containing the active compound(s) suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, e-lauryl sulphate, an alcohol (e.g. ethanol, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol) and water.
  • a suitable gel containing the active compound(s) suspended or dissolved in, for example, a mixture of one or more of the following: a natural polymer (e.g.
  • a protein such as gelatin, casein, collagen, and egg whites
  • a polysaccharide such as guar gum, acacia, tragacanth, bug bean gum, pectin, starch, xanthan gum, dextran, succinoglucon
  • a semisynthetic polymer e.g. a cellulose subordinate (such as carboxymethyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose and, particularly, hydroxypropylcellulose), magnesium aluminium silicate or sodium alginate), a synthetic polymer (e.g.
  • the medicament e.g. lotion, solution, cream, gel or ointment
  • the medicament may also be administered intranasally or by inhalation and may be conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of formula (I) or (II) and a suitable powder base such as lactose or starch.
  • the methods of the invention may involve exposing bacteria to both a first and second antibacterial agent, as defined herein. The use of such agents in combination is found to particularly effective at suppressing the emergence of antibacterial resistance.
  • the first and second antibacterial agents may be administered concomitantly or sequentially.
  • first and second antibacterial agents are administered simultaneously.
  • the first and second antibacterial agents may also be provided in a single pharmaceutical composition or may be provided in separate pharmaceutical compositions. References herein to “combinations” therefore include references to a single formulation which contains both the first and second antibacterial agent, and also to the provision of the first and second antibacterial agents in different formulations.
  • a combination comprising first antibacterial agent which is a compound of formula (I) or formula (II) as defined herein, and a second antibacterial agent. Said combination may be useful in the treatment or prevention of a bacterial infection, wherein the use of the combination suppresses the emergence of antibiotic resistance.
  • the first and second antibacterial agents may be provided in a single pharmaceutical composition or may be provided in separate pharmaceutical compositions.
  • Particular first antibacterial agents that may be mentioned in this respect include 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride and 5,15-bis-[3-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride.
  • Particular second antibacterial agents that may be mentioned in this respect include rumblemulin and mupirocin.
  • the combination may comprise a first antibacterial agent selected from 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride and 5,15-bis-[3-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride, and a second antibacterial agent selected from fusidic acid, rumblemulin and mupirocin, optionally wherein the first and second antibacterial agents are provided in a single pharmaceutical composition.
  • a first antibacterial agent selected from 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride and 5,15-bis-[3-(3-trimethylammonio-propyloxy)-phenyl]-porphyrin dichloride
  • a second antibacterial agent selected from fusidic acid, rumblemulin and mupirocin
  • kit-of-parts comprising components: (A) a pharmaceutical formulation comprising a compound of formula (I) or (II), and optionally one or more pharmaceutically-acceptable excipients; and (B) a pharmaceutical formulation comprising the second antibacterial agent, such as mupirocin, and optionally one or more pharmaceutically-acceptable excipients, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
  • Said kit-of-parts may be useful in the treatment or prevention of a bacterial infection, wherein the use of the kit suppresses the emergence of antibiotic resistance.
  • kits-of-parts described herein By “administration in conjunction with” (and similarly “administered in conjunction with”) we include that respective formulations comprising the first and second antibacterial agents are administered, sequentially, separately or simultaneously, as part of the same medical intervention. Therefore, in relation to the present invention, the term “administration in conjunction with” (and similarly “administered in conjunction with”) includes that the two active ingredients (i.e.
  • the compound of formula (I) or (II), and the second antibacterial agent) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising a compound of formula (I) or (II), or a formulation comprising a second antibacterial agent are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment.
  • the first and second antibacterial agents are administered together.
  • the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component.
  • a treatment regime which involves administration of mupirocin alongside administration of XF-73, with both administration regimes co-existing for a continuous period of at least 24 hours.
  • Mupirocin is typically administered up to 3 times daily and XF- 73 is typically administered up to four times daily, consequently the time points when individual doses of the two components are administered may not always coincide.
  • the terms “administered simultaneously” and “administered at the same time as” include such administration regimes.
  • the individual doses of a compound of formula (I) or (II) and a second antibacterial agent are administered within 1 hour (e.g. within 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.
  • references to “sequential administration” may refer to separate administration of the therapeutic agents as part of the same medical intervention (e.g. within four hours, such as within two hours or, particularly within one hour, of each other).
  • a kit-of-parts comprising: (I) one of components (A) or (B) as described in the previous aspect of the invention; and (II) instructions to use that component in combination with the other of the two components, for use in treating or preventing a bacterial infection, wherein the use suppresses the emergence of antibiotic resistance.
  • pharmaceutical formulations including those containing more than one active ingredient as described herein may be prepared using techniques known to those skilled in the art.
  • kits-of-parts may be prepared using techniques known to those skilled in the art.
  • the first and second antibacterial agents may be administered at varying therapeutically effective doses (to the relevant patient in need thereof). Suitable doses may be determined by the skilled person using routine techniques, such as by routine dose titration studies and the like.
  • therapeutically effective doses and similar terms such as “effective amount” refer to an amount that is effective to suppress resistance emergence.
  • the amount of the first and second antibacterial agents included in the relevant pharmaceutical formulations may be determined based on the desired dosage of the first or second antibacterial agent, as appropriate, the ease of formulation and the route of administration (which may in turn determine the availability of the first or second antibacterial agent for systemic absorption).
  • the medicament comprising the compound of formula (I) or (II) may be formulated at various concentrations, depending on the efficacy/toxicity of the compound being used and the indication for which it is being used.
  • the medicament comprises the compound at a concentration of from about 0.1 to about 5,000 mg/L, such as from about 0.1 to about 2,000 mg/L (e.g. about 0.1 to about 500 mg/L).
  • Topical formulations may be administered directly at the site of need using an amount conventional for a topical ointment or other topical formulation. Doses may be repeated as necessary, such as in the form of periodic, sequential applications. For example, the doses may be administered once or twice per day for several days (e.g. from 1 to 21 days, such as from 3 to 14 days, preferably for around 5 to 10 days). In one embodiment, the compound of formula (I) or (II) and the second antibacterial agent are administered together twice daily for five days.
  • the preferred dosage frequency for the second antibacterial agent is the dosage frequency prescribed in approved commercial product labels.
  • Fucidin (fusidic acid) may be provided as a 20 mg/g cream which is administered to affected skin three to four times per day.
  • Rumblemulin may be provided as a 1% ointment which is administered to affected skin twice daily for five days.
  • Mupirocin ointment may be provided as a 20 mg/g ointment which is administered to affected skin three times per day for up to ten days.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains at least 1 mg of a compound of formula (I) or (II) for delivery to the patient. It will be appreciated that the overall dose with an aerosol will vary from patient to patient and from indication to indication, and may be administered in a single dose or, more usually, in divided doses throughout the day.
  • Mupirocin nasal ointment may be provided as a 2 wt% ointment which is administered to the nose (0.5g of ointment administered to each nostril) twice daily for 5 days.
  • the dosage frequency of the compound of formula (I) or (II) may be matched with that of the second antibacterial agent, i.e. in line with any of the dosage frequencies described here, or vice versa.
  • dose of compounds of formula (I) or (II) administered should be sufficient to effect the desired therapeutic response or preventative effect within (and over) a reasonable timeframe.
  • each of the first and second antibacterial agents may be intermittent (e.g. through periodic application of an ointment), or may be provided in the form of a single dose (e.g. by a single application of an ointment).
  • the dosage form may also be determined by the timing and frequency of administration, and vice versa. Where the first and second antibacterial agents are not provided in the same formulation, they may be administered at different times and/or at different frequencies.
  • the first antibacterial agent may be administered twice per day, whilst the second antibacterial agent is administered once per day.
  • the word “about” is employed herein, for example in the context of amounts (e.g. doses of active ingredients), it will be appreciated that such variables are approximate and as such may vary by ⁇ 10%, for example ⁇ 5% and preferably ⁇ 2% (e.g. ⁇ 1%) from the numbers specified herein.
  • all embodiments and particular features described in relation to particular aspects of the invention (and combinations thereof) will also apply to all other aspects of the invention, as appropriate.
  • Figure 1 shows a graphical representation of mupirocin and mupirocin–XF-73 MIC values by day during serial passaging (log 2 MIC scale).
  • XF-73 was present at a fixed 0.12 mg/L, where indicated.
  • Figure 2 shows a graphical representation of mupirocin and mupirocin–XF-73 MIC values by day during serial passaging (linear MIC scale).
  • XF-73 was present at a fixed 0.12 mg/L, where indicated.
  • Figure 3 shows a comparison of fold increases in mupirocin MIC values of purified terminal strains after serial passaging.
  • Example 1 Reduction of mupirocin resistance emergence using XF-73 The ability of sub-MIC levels of 5,15-bis-[4-(3-trimethylammonio-propyloxy)-phenyl]- porphyrin dichloride (referred to here as XF-73) to reduce the in vitro development of mupirocin resistance when a methicillin-resistant Staphylococcus aureus (MRSA) clinical isolate was subjected to serial passaging in the presence of mupirocin–XF-73 combinations was evaluated.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Low-level mupirocin resistance (MIC, 8-256 mg/L) has also been described, and is usually due to the selection of various mutations within the intrinsic ileS gene [Hurdle et al., ibid.].
  • This study was concerned with the development of low-level mupirocin resistance. Isolates were tested for antimicrobial susceptibility using broth microdilution methodology per CLSI guidelines [CLSI.2019 ibid.; CLSI. 2018. M07Ed11. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: eleventh edition. Clinical and Laboratory Standards Institute, Wayne, PA].
  • the testing medium was cation-adjusted Mueller-Hinton broth (CAMHB).
  • serial Passaging with Mupirocin and Mupirocin–XF-73 Combinations A total of 5 independent cultures of MRSA isolate #1034046 were subjected to serial passaging in the presence of increasing concentrations of mupirocin, and an additional 5 independent cultures were subjected to serial passaging in the presence of increasing concentrations of mupirocin with XF-73 present at a fixed concentration of 0.12 mg/L. On each day of serial passaging, the MIC value for each independent culture was recorded from the previous day’s serial passaging panel.
  • the material from the well 1 dilution below the MIC value was harvested and used to inoculate 5.5 mL of CAMHB, which was grown for ⁇ 3 hours at 35°C with aeration. Each culture was then diluted and added to the next serial passaging panel such that a cell concentration of ⁇ 5 x 10 5 CFU/mL was achieved in each well. The serial passaging panel was then grown at 35°C without aeration for 16-20 hours. Multiple inocula from the isolate were independently passaged daily for 50 days in the presence of mupirocin or a combination of mupirocin plus a sub-MIC concentration of XF- 73.
  • Mupirocin and XF-73 (at a fixed concentration of 0.12 mg/L): The MIC values that were observed for 5 independent cultures of MRSA #1034046 during serial passaging in the presence of mupirocin–XF-73 (fixed 0.12 mg/L) are shown in Table 2 and Figures 1 and 2. Unlike the results obtained with mupirocin alone, the mupirocin–XF-73 (fixed 0.12 mg/L) MIC values varied little during the course of the serial passaging.
  • the modal MIC value for mupirocin–XF-73 (fixed 0.12 mg/L) against the parental isolate #1034046 was 0.06 mg/L and the majority of MIC values that were measured during serial passaging were within 1 dilution of the starting modal MIC.
  • the cultures with the highest terminal MIC values for the combination were #2 (0.25 mg/L) and #4 (0.25 mg/L) (Table 2). Both strains that were purified from each terminal culture exhibited similar MIC values, which suggested that each terminal culture was relatively homogenous in phenotype.
  • the mupirocin MIC values against the purified terminal strains were identical to the parent isolate for 1 strain, 2-fold higher for 5 strains, 4-fold higher for 2 strains, and 8-fold higher for 2 strains (Table 3 and Figure 3).
  • the XF-73 MIC values exhibited by the purified terminal strains were identical to the parent isolate (Table 3).
  • MRSA isolate #1034046 was serially passaged in the presence of mupirocin, which increased the mupirocin MIC values of the terminal strains by 4- to 128-fold (Figure 3).
  • mupirocin MIC values of the terminal purified strains passaged in the presence of mupirocin–XF-73 combinations generally also increased, the magnitude of the effect was significantly smaller ( ⁇ 2- to 8-fold; Figure 3).
  • the presence of XF-73 therefore helped suppress the development of mupirocin resistance when isolate #1034046 was subjected to 50 days of serial passaging in vitro.

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Abstract

L'invention concerne l'utilisation d'un composé de formule (I) ou de formule (II) telles que définies ici pour inhiber l'émergence d'une résistance aux antibiotiques dans des bactéries exposées à un autre agent antibactérien (par exemple la mupirocine). L'invention concerne également une combinaison comprenant un composé de formule (I) ou de formule (II) telles que définies dans la description et un second agent antibactérien (par exemple la mupirocine) pour traiter ou prévenir une infection bactérienne, dans laquelle l'utilisation de la combinaison inhibe l'émergence d'une résistance aux antibiotiques. De telles infections bactériennes peuvent être provoquées par Staphylococcus aureus ou Streptococcus pyogenes, par exemple le MRSA.
PCT/GB2022/050477 2021-02-23 2022-02-22 Combinaison de mupirocine avec des photosensibilisateurs à base de porphyrine pour réduire l'émergence d'une résistance aux antibiotiques WO2022180380A1 (fr)

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