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US-20260124268-A1 - QUORUM-SENSING INHIBITORS AND/OR POSTBIOTIC METABOLITES AND RELATED METHODS

US20260124268A1US 20260124268 A1US20260124268 A1US 20260124268A1US-20260124268-A1

Abstract

Described herein is a synergistic combination comprising a quorum-sensing inhibitor and/or postbiotic metabolite and an antibiotic. Typically, the postbiotic metabolite comprises at least one peptide. Related compositions, uses, and methods are also described, including methods for resensitizing resistant bacteria to an antibiotic, and methods of treating antibiotic-resistant infections, such as methicillin-resistant Staphylococcus aureus (MRSA).

Inventors

  • Monica Angela Cella

Assignees

  • MICROSINTESIS INC.

Dates

Publication Date
20260507
Application Date
20250617

Claims (20)

  1. 1 . A synergistic combination comprising a quorum-sensing inhibitor and/or a postbiotic metabolite and an antibiotic.
  2. 2 . The synergistic combination of claim 1 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite comprises a peptide, small molecule, lipid, sugar, or a combination thereof.
  3. 3 . The synergistic combination of claim 2 , wherein the peptide comprises or consists of one or more of the following amino acid sequences: XX [L or I] PPK, wherein X designates a hydrophobic amino acid; X 1 X 2 [L or I] PPK, wherein X 1 is selected from N, C, Q, M, S, and T and wherein X 2 is selected from A, I, L, and V; MALPPK; CVLPPK; HLLPLP; LKPTPEGD; YPVEPF; YPPGGP; YPPG; NOPY; LPVPK; ALPK; EVLNCLALPK; LPLP; HLLPLPL; YVPEPF; KYVPEPF; EMPFKPYPVEPF; and variants thereof altered by deletion, substitution or insertion wherein the activity of the molecules is not substantially reduced, including peptides and/or variants thereof with post-translational modifications including glycosylation.
  4. 4 . The synergistic combination of claim 1 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite is a peptide and comprises or consists of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues, such as from 2, 3, 4, 5, 6, 7, 8, or 9 to about 3, 4, 5, 6, 7, 8, 9, or 10 amino residues.
  5. 5 . The synergistic combination of claim 1 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite is less than about 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, or 500 Da in size, such as less than about 3000, 2000, or 1000 Da in size.
  6. 6 . The synergistic combination of claim 1 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite is in a probiotic bacterial culture fraction, such as a supernatant.
  7. 7 . The synergistic combination of claim 6 , wherein the probiotic bacterial culture fraction is a cell-free spent medium (CSFM), which is optionally concentrated in liquid or dry form.
  8. 8 . The synergistic combination of claim 7 , wherein the CSFM has a molecular weight cut-off of about 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, or 500 Da in size, such as about 3000, 2000, or 1000 Da.
  9. 9 . The synergistic combination of claim 1 , wherein the antibiotic is an aminoglycoside, a bacitracin, a beta-lactam antibiotic, a cephalosporin, a chloramphenicol, a glycopeptide, a macrolides, a lincosamide, a penicillin, a quinolone, a rifampin, a glycopeptide, a tetracycline, a trimethoprim, a sulfonamides, or a combination thereof.
  10. 10 . The synergistic combination of claim 9 , wherein the antibiotic is a β-lactam antibiotic, such as cefoxitin.
  11. 11 . The synergistic combination of claim 1 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite is derived from the culture medium or supernatant of probiotic bacteria of the genera Aerococcus, Bacillus, Bacteroides, Bifidobacterium, Clostridium, Enterococcus, Fusobacterium, Lactobacillus, Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Pediococcus, Peptostrepococcus, Propionibacterium, Staphylococcus, Streptococcus , Weissella, or combinations thereof.
  12. 12 . The synergistic combination of claim 11 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite is derived from Lactobacillus , such as Lactobacillus acidophilus , such as Lactobacillus acidophilus (DSM13241) and/or wherein the quorum-sensing inhibitor and/or postbiotic metabolite is derived from Enterococcus , such as Enterococcus faecium.
  13. 13 . The synergistic combination of claim 1 , further comprising a probiotic.
  14. 14 . The synergistic combination of claim 13 , wherein the probiotic is of the genera Aerococcus, Bacillus, Bacteroides, Bifidobacterium, Clostridium, Enterococcus, Fusobacterium, Lactobacillus, Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Pediococcus, Peptostrepococcus, Propionibacterium, Staphylococcus, Streptococcus , Weissella, or combinations thereof.
  15. 15 . The synergistic combination of claim 14 , wherein the probiotic is Lactobacillus , such as Lactobacillus acidophilus , such as Lactobacillus acidophilus (DSM13241) and/or Enterococcus , such as Enterococcus faecium.
  16. 16 . The synergistic combination of claim 13 , wherein the probiotic is live.
  17. 17 . The synergistic combination of claim 13 , wherein the probiotic is present in an amount of about 100 million to about 500 million CFU per dose, such as about 200 million CFU per dose.
  18. 18 . A composition comprising the synergistic combination of claim 1 .
  19. 19 . A method for: (a) resensitizing an antibiotic-resistant infection to an antibiotic, the method comprising administering a quorum-sensing inhibitor and/or a postbiotic metabolite to a subject afflicted with the infection; (b) decreasing resistance of a bacterial infection to hydrogen peroxide cytotoxicity, the method comprising administering a quorum-sensing inhibitor and/or a postbiotic metabolite to a subject afflicted with the infection; (c) treating and/or preventing diarrhea in a subject, the method comprising administering a quorum-sensing inhibitor and/or a postbiotic metabolite and an antibiotic to the subject; (d) treating MRSA or MRSP, the method comprising administering a quorum-sensing inhibitor and/or a postbiotic metabolite and an antibiotic to a subject afflicted with MRSA or MRSP; (e) reducing carotenoid synthesis in bacteria, the method comprising administering a quorum-sensing inhibitor and/or a postbiotic metabolite to the bacteria; and/or (f) sensitizing bacteria to oxidant killing, the method comprising administering a quorum-sensing inhibitor and/or a postbiotic metabolite to the bacteria.
  20. 20 . The method of claim 19 , wherein the quorum-sensing inhibitor and/or postbiotic metabolite and the antibiotic act synergistically.

Description

PRIORITY STATEMENT This application is a continuation of U.S. application Ser. No. 17/624,455, filed Jan. 3, 2022, which is a 35 U.S.C. § 371 national phase application of International Application Serial No. PCT/CA2020/050921, filed Jul. 2, 2020, which claims the benefit under 35 U.S.C. § 119 (a) of U.S. Application No. 62/869,681, filed Jul. 2, 2019, the entire contents of each of which are incorporated by reference herein. STATEMENT REGARDING ELECTRONIC FILING OF A SEQUENCE LISTING A Sequence Listing in XML format, entitled 1360-32CT_ST26.xml, 16,694 bytes in size, generated on Jun. 17, 2025, and filed herewith, is hereby incorporated by reference into the specification for its disclosures. FIELD The present invention relates to quorum-sensing inhibitors and/or postbiotic metabolites. More specifically, the present invention is, in aspects, concerned with quorum-sensing inhibitors and/or postbiotic metabolites as alternatives to antibiotics, combinations of quorum-sensing inhibitors and/or postbiotic metabolites with antibiotics, and related compositions and methods. BACKGROUND A World Health Organization (WHO) report released April 2014 stated, “this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance—when bacteria change so antibiotics no longer work in people who need them to treat infections—is now a major threat to public health.” The European Centre for Disease Prevention and Control calculated that in 2015 there were 671,689 infections in the EU and European Economic Area caused by antibiotic-resistant bacteria, resulting in 33,110 deaths. Most were acquired in healthcare settings. The World Health Organization concluded that inappropriate use of antibiotics in animal husbandry is an underlying contributor to the emergence and spread of antibiotic-resistant germs, and that the use of antibiotics as growth promoters in animal feeds should be restricted. The World Organisation for Animal Health has added to the Terrestrial Animal Health Code a series of guidelines with recommendations to its members for the creation and harmonization of national antimicrobial resistance surveillance and monitoring programs, monitoring of the quantities of antibiotics used in animal husbandry, and recommendations to ensure the proper and prudent use of antibiotic substances. Another guideline is to implement methodologies that help to establish associated risk factors and assess the risk of antibiotic resistance. Since the discovery of antibiotics, research and development (R&D) efforts have provided new drugs in time to treat bacteria that became resistant to older antibiotics, but in the 2000s there has been concern that development has slowed enough that seriously ill people may run out of treatment options. Another concern is that doctors may become reluctant to perform routine surgeries because of the increased risk of harmful infection. International Patent Application Publication Nos. WO 2009/155711, WO 2015/021530, 2018/165764, and WO 2018/165765 describe certain postbiotic metabolites that are found in the cell-free spent medium (CFSM) of probiotic cultures. These postbiotic metabolites have been shown to be effective in treating a number of different infections, including bacterial and viral infections of many different origins and in different species. Despite this, there remains a need for alternatives to conventional antibiotics and methods for treating infection. DESCRIPTION OF THE DRAWINGS The present invention will be further understood from the following description with reference to the Figures, in which: FIG. 1A: Heat plot of MIC percent growth inhibition of the clinical MRSA strain MRSA 81M (n=3) by combination testing of the β-lactam antibiotic cefoxitin (0-100 μg/mL) and DSM13241 bioactive metabolites (5, 30, and 60 mg/mL). MRSA strain MRSA 81M was proven to have methicillin resistance via cefoxitin testing (MIC≥8 μg/mL). All biological replicates were performed with technical duplicates. FIG. 1B: Heat plot of MIC percent growth inhibition of the clinical MRSA strain MRSA LA (n=3) by combination testing of the β-lactam antibiotic cefoxitin (0-100 μg/mL) and DSM13241 bioactive metabolites (5, 30, and 60 mg/mL). MRSA strain MRSA LA was proven to have methicillin resistance via cefoxitin testing (MIC≥8 μg/mL). All biological replicates were performed with technical duplicates. FIG. 1C: Bar graph of FIC index values for analysis of the combinatory effect of the bioactive metabolites and cefoxitin. Synergy of the bioactive material was evident as the individual MICs for MRSA 81M and MRSA LA were 100 μg/mL and 60 μg/mL, respectively, and all concentrations of bioactive material (5, 30, and 60 mg/mL) elicited either an additive (FIC>0.5-1.0) or synergistic (FIC≤0.5) effect to reduce the concentration of cefoxitin needed to elicit a growth inhibitory MIC r