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EP-4736859-A1 - ANTIBIOTIC COMPOSITIONS

EP4736859A1EP 4736859 A1EP4736859 A1EP 4736859A1EP-4736859-A1

Abstract

The invention relates to an antibiotic composition comprising or consisting of: a purine nucleoside selected from guanosine and xanthosine, or a combination thereof; and an inhibitor of thymidine and/or pyrimidine biosynthesis. A further combination with a Beta-lactam antibiotic can be provided. The invention further relates to associated kits, methods and uses in treatment.

Inventors

  • O'Gara, James P
  • Nolan, Aaron C
  • Zeden, Merve S
  • CAMPBELL, CHRISTOPHER

Assignees

  • University of Galway

Dates

Publication Date
20260506
Application Date
20241101

Claims (20)

  1. An antibiotic composition comprising or consisting of: a purine nucleoside selected from guanosine and xanthosine, or a combination thereof; and an inhibitor of thymidine and/or pyrimidine biosynthesis.
  2. The antibiotic composition according to claim 1, further comprising a β-lactam antibiotic.
  3. The antibiotic composition according to claim 2, wherein the β-lactam antibiotic is selected from methicillin, oxacillin, nafcillin, cefoxitin, cefotaxime, cefaclor, penicillin G, and cloxacillin, or variants thereof.
  4. The antibiotic composition according to claim 2 or 3, wherein the β-lactam antibiotic is provided in an amount of from 7% to 33 % w/v of the composition.
  5. The antibiotic composition according to any of claims 2-4, wherein the β-lactam antibiotic, is provided in the composition at a concentration of from 25 mg/kg to 300 mg/kg.
  6. The antibiotic composition according to any preceding claim, wherein the purine nucleoside is provided in an amount of from about 30% to about 90 % w/v of the composition.
  7. The antibiotic composition according to any preceding claim, wherein the purine nucleoside may be provided in the composition at a concentration up to about 960mg/kg or 1g/L in solution.
  8. The antibiotic composition according to any preceding claim, wherein the inhibitor of thymidine and/or pyrimidine biosynthesis comprises an agent that inhibits one or more of dihydroorotate dehydrogenase (DHODH), aspartate transcarbamoylase (ATCase), dihydrofolate reductase (DHFR), carbamoyl phosphate synthetase II (CPS II), thymidylate synthase (TS), orotindine 5'-monophosphate decarboxylase (ODCase), and folate metabolism.
  9. The antibiotic composition according to any preceding claim, wherein the inhibitor of thymidine and/or pyrimidine biosynthesis is selected from 5-fluorouracil (5-FU), 5-fluorouridine (5-FUrd), sulfamethoxazole (SMX), trimethoprim (TMP), and combinations thereof, or variants thereof.
  10. The antibiotic composition according to any preceding claim, wherein the inhibitor of thymidine and/or pyrimidine biosynthesis comprises a combination of sulfamethoxazole and trimethoprim (SMX-TMP).
  11. The antibiotic composition according to any preceding claim, wherein the inhibitor of thymidine and/or pyrimidine biosynthesis is provided in the composition at a concentration of from about 7% to about 33% w/v.
  12. The antibiotic composition according to any one of claims 2-11, wherein the β-lactam antibiotic, the purine nucleoside, and the inhibitor of thymidine or pyrimidine biosynthesis, are provided in a ratio from about 1:1:1 to about 1:14:1 (w/w).
  13. A kit, wherein the kit comprises or consists of: a) a purine nucleoside selected from guanosine and xanthosine, or a combination thereof; and b) one or more inhibitors of thymidine and/or pyrimidine biosynthesis.
  14. The kit according to claim 13, wherein the kit further comprises c) a β-lactam antibiotic.
  15. An antibiotic composition according to any of claims 1-12, or a kit according to claims 13 or 14, for use as a medicament.
  16. Use of the composition according to any of claims 1-12, or a kit according to claims 13 or 14 in the manufacture of a medicament.
  17. The antibiotic composition or the kit according to claim 15, or the use according to claim 16, wherein the medicament is for use to treat or prevent a bacterial infection or colonisation of a subject.
  18. A method of treatment or prevention of a bacterial infection or colonisation of a subject, the method comprising administration of the antibiotic composition according to the invention to the subject, or the administration of: a) a purine nucleoside selected from guanosine and xanthosine, or a combination thereof; and b) an inhibitor of thymidine and/or pyrimidine biosynthesis, to the subject.
  19. The method according to claim 18, further comprising the administration of a β-lactam antibiotic.
  20. A method of reducing resistance to a β-lactam antibiotic in a bacterium, the method comprising the administration of the composition according to any of claims 1-12, or the kit according to claims 13 or 14, to the bacterium.

Description

Technical Field The present invention relates to antibiotic compositions suitable for the treatment of bacterial infections, particularly wherein the infections are caused by antibiotic-resistant bacteria, and related products, uses, and methods of treatment. Introduction Antimicrobial resistance (AMR) is a troubling burden on worldwide health, and it is predicted that by 2050, 10 million deaths per year could be caused by pathogens with increasing rates of AMR. Staphylococcus aureus infections are one of the leading pathogens for death toll each year categorised in the ESKAPE pathogen category, and of these deaths majority are caused by methicillin resistant S. aureus (MRSA). MRSA is resistant to majority of β-lactam antibiotics on the market which is considered the gold standard for treating S. aureus infections, although there are alternative treatment strategies for MRSA such as vancomycin and daptomycin, they have high treatment failure rates. The rising levels of increasing resistance seen due to MRSA infections is leading to novel treatment strategies being considered to treat potentially life-threatening bacterial infections with dwindling choices of antibiotics for therapeutic intervention. The imminent threat of AMR infections has called upon novel strategies such as bacteriophage therapy, new antibiotic development, identifying novel therapeutic targets and antibiotic adjuvants. Adjuvants can re-sensitise MRSA to antibiotic treatment as shown recently by our group by disrupting cyclic-di-adenosine-monophosphate (c-di-AMP) levels in MRSA increasing beta-lactam susceptibility (1, 2). Nolan et al. (2023. mBio 14:e02478-22. https://doi.org/10.1128/mbio.02478-22 - herein incorporated by reference) is a research article that investigates how purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitize MRSA to β-lactam antibiotics. It demonstrates how using purine nucleosides as adjuvants to increase the susceptibility of clinically important pathogens to β-lactams has the potential to facilitate new treatments with lower antibiotic doses and with drug combinations that are toxic at higher concentrations. In vitro kill curves revealed significant bactericidal activity using combinations of guanosine and oxacillin (OX) at concentrations up to 128 µg/mL, which are within the range of flucloxacillin intravenously administered to human patients (100-200 mg/kg/day). While the emergence of OX/Gua suppressor mutants appeared to be significantly reduced at higher oxacillin concentrations (as evidenced by the absence of re-growth in kill curve cultures), this remains a potential barrier to the use of nucleosides as β-lactam adjuvants. Therefore, further new treatments are required to optimise purine nucleosides as adjuvants and to further increase the effectiveness of anti-microbials, such as β-lactams. Summary of the Invention According to a first aspect of the invention, there is provided an antibiotic composition comprising or consisting of: a β-lactam antibiotic;a purine nucleoside selected from guanosine and xanthosine, or a combination thereof; andan inhibitor of thymidine and/or pyrimidine biosynthesis. According to another aspect of the invention, there is provided an antibiotic composition comprising or consisting of: guanosine or xanthosine; andan inhibitor of thymidine and/or pyrimidine biosynthesis. The antibiotic composition may be for killing or inhibiting the growth of a targeted bacterium. The inventors have identified that it is possible to restore susceptibility to a β-lactam antibiotic in a β-lactam-resistant bacterium by interfering with its endogenous thymidine biosynthetic pathway. Advantageously, the present invention may reduce resistance to β-lactam antibiotics in planktonic bacteria and in biofilms. Further advantageously, the present invention can significantly reduce the minimum inhibitory concentration (MIC) of a β-lactam antibiotic by exploiting newly identified synergies between 1. the β-lactam antibiotic, a purine nucleoside, and an inhibitor of thymidine biosynthesis.2. the purine nucleoside guanosine and sulfamethoxazole, which is required for production of tetrahydrofolate, a co-factor in thymidine biosynthesis.3. a triple combination of the purine nucleoside guanosine, sulfamethoxazole and 5-fluorouracil, which interferes with pyrimidine biosynthesis. Further advantageously, the present invention can significantly enhance killing of viable planktonic bacteria by combinations of antibiotics (e.g., β-lactams, SMX, TMP, 5-FU and 5-FUrd) over 12-24 hours at concentrations of the agents that would normally be insufficient when used alone. A further advantage has been identified in that guanosine and/or xanthosine combined with a thymidine synthesis inhibitor, such as 5-FU, and/or a pyrimidine synthesis inhibitor, such as SMX, demonstrates a surprisingly high level of anti-bacterial activity, particularly anti-MRSA killing activity. The Purine Nucleoside Th