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US-12624127-B2 - Chitosan derivatives as antimicrobials and synergistic combinations thereof

US12624127B2US 12624127 B2US12624127 B2US 12624127B2US-12624127-B2

Abstract

Disclosed herein is a compound of formula I: where m, n and R 1 are as defined herein. Also disclosed herein are uses of the compound.

Inventors

  • Bee Eng Mary Chan
  • Zhangyong SI
  • Zheng Hou
  • Yogesh Shankar Vikhe
  • Kishore Reddy Venkata Thappeta

Assignees

  • NANYANG TECHNOLOGICAL UNIVERSITY

Dates

Publication Date
20260512
Application Date
20220414

Claims (17)

  1. 1 . A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, an antibiotic or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, where the compound of formula I is: where: the sum of m and n is 1 and each of m and n is from 0.1 to 0.9; each R 1 is selected from NH 2 and NH—(CH 2 ) a —X; a is 2 to 3; X is selected from O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH 2 , NH 2 , NH—(CH 2 ) b —Y and N((CH 2 ) c —NH 2 ) 2 ; b and c are each independently selected from 2 to 4, Y is selected from NH 2 or NH—(CH 2 ) d —NH 2 , d is selected from 2 to 4, and wherein the antibiotic is selected from the group consisting of ampicillin, carbenicillin, meropenem, novobiocin, tobramycin, amikacin, tazobactam, and rifampicin.
  2. 2 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients and adjuvants.
  3. 3 . The pharmaceutical composition of claim 1 , wherein m is 0.8 and n is 0.2.
  4. 4 . The pharmaceutical composition of claim 1 , wherein the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is selected from the list:
  5. 5 . The pharmaceutical composition of claim 1 wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is:
  6. 6 . The pharmaceutical composition of claim 1 , wherein the compound of formula I has a number-average molecular weight of from 7,000 to 15,000 Da.
  7. 7 . The pharmaceutical composition of claim 6 , wherein the compound of formula I has a number-average molecular weight of about 12,850 Da.
  8. 8 . The pharmaceutical composition of claim 1 , wherein the compound of formula I has a polydispersity of from 1.0 to 2.0, as measured using gel permeation chromatography.
  9. 9 . A kit of parts comprising: (a) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, where the compound of formula I is: where: the sum of m and n is 1 and each of m and n is from 0.1 to 0.9; each R 1 is selected from NH 2 and NH—(CH 2 ) a —X a is 2 to 3; X is selected from O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH 2 , NH 2 , NH—(CH 2 ) b —Y and N((CH 2 ) c —NH 2 ) 2 b and c are each independently selected from 2 to 4, Y is selected from NH 2 or NH—(CH 2 ) d —NH 2 , d is selected from 2 to 4; and (b) a pharmaceutical composition comprising an antibiotic or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, wherein the antibiotic is selected from the group consisting of ampicillin, carbenicillin, meropenem, novobiocin, tobramycin, amikacin, tazobactam, and rifampicin.
  10. 10 . The kit of parts according to claim 9 , wherein each of the pharmaceutical compositions further comprises one or more pharmaceutically acceptable excipients and adjuvants.
  11. 11 . The kit of parts of claim 9 , wherein m is 0.8 and n is 0.2.
  12. 12 . The kit of parts of claim 9 , wherein the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is selected from the list:
  13. 13 . The kit of parts of claim 9 , wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is:
  14. 14 . The kit of parts of claim 9 , wherein the compound of formula I has a number-average molecular weight of from 7,000 to 15,000 Da.
  15. 15 . The kit of parts of claim 14 , wherein the compound of formula I has a number-average molecular weight of about 12,850 Da.
  16. 16 . The kit of parts of claim 9 , wherein the compound of formula I has a polydispersity of from 1.0 to 2.0, as measured using gel permeation chromatography.
  17. 17 . A method of treating a microbial infection in a subject, the method comprising administering a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and an antibiotic or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is administered sequentially, simultaneously or concomitantly with the antibiotic, and wherein the compound of formula I is: where: the sum of m and n is 1 and each of m and n is from 0.1 to 0.9; each R 1 is selected from NH 2 and NH—(CH 2 ) a —X a is 2 to 3; X is selected from O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH 2 , NH 2 and NH—(CH 2 ) b —Y, N((CH 2 ) c —NH 2 ) 2 ; b and c are each independently selected from 2 to 4, Y is selected from NH 2 or NH—(CH 2 ) d —NH 2 , d is selected from 2 to 4, and wherein the antibiotic is selected from the group consisting of ampicillin, carbenicillin, meropenem, novobiocin, tobramycin, amikacin, tazobactam, and rifampicin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to, and the benefit of, Singapore Patent Application SG10202103862T, filed on Apr. 15, 2021, which is incorporated by reference as if set forth herein in its entirety. FIELD OF INVENTION The current invention relates to derivatives of chitosan, which display an antimicrobial effect—not only when applied as the only active ingredient, but also provides a synergistic antimicrobial effect when used in combination with another antimicrobial compound. BACKGROUND The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Nowadays, the development of bacteria resistance towards antibiotics is emerging as a severe healthcare problem. After decades of antibiotic abuse as drugs or detergents, bacteria have developed antibiotic resistance mechanisms, such as alternating the target protein of the antibiotics, secreting enzymes to degrade the antibiotics, changing membrane permeability to prevent antibiotics influx, and developing membrane efflux pumps to exclude the antibiotics inside bacteria. The bacterial cell membranes function as barriers for antibiotics. Inspired by natural antimicrobial peptides, membrane-targeting cationic antimicrobial polymers provide a novel approach in curing bacterial infection (B. Findlay, G. G. Zhanel & F. Schweizer, Antimicrob. Agents Chemother. 2010, 54, 4049-4058). Combined with the hydrophobic moiety, the cationic polymer can interrupt cytoplasmic membrane and cause the leakage of cytosol, resulting in the death of bacteria (C. Ergene, K. Yasuhara & E. F. Palermo, Polym. Chem. 2018, 9, 2407-2427). However, the reported cationic antimicrobial polymers have low biocompatibility in general as measured by high hemolytic activity and cytotoxicity towards mammalian cells (J. Cai et al., Macromolecules 2011, 44, 2050-2057). Although the progress in this area has discovered some biocompatible cationic antimicrobial polymers based on polycarbonate (W. Chin et al., Nat. Commun. 2018, 9, 1-14), α-peptide (S. J. Lam et al., Nat. Microbiol. 2016, 1, 1-11), β-peptide (M. Zhou et al., Angew. Chem. Int. Ed. 2020, 59, 7240-7244), polyaspartamide (S. Yan et al., Adv. Funct. Mater. 2019, 29, 1904683), poly(2-oxazoline) (M. Zhou et al., Angew. Chem. Int. Ed. 2020, 59, 6412-6419), etc., most of them share the general design principle of balanced cationic and hydrophobic residues. Therefore, it is critical to search and develop cationic antimicrobial polymers with good biocompatibility based on new design. Chitosan is a cationic polysaccharide derived from chitin, the main component in many natural materials. Chitosan has certain amount of antimicrobial activity via membrane interruption (E. I. Rabea et al., Biomacromolecules 2003, 4, 1457-1465; and M. S. Benhabiles et al., Food Hydrocoll. 2012, 29, 48-56) and has been applied as a defensive material to different animals in agriculture (Z. Ma, A. Garrido-Maestu & K. C. Jeong, Carbohydr. Polym. 2017, 176, 257-265). Various forms of chitosan and its derivatives such as pure chitosan (M. Kong et al., Int. J. Food Microbiol. 2010, 144, 51-63), quaternary ammonium chitosan (J. Vins̆ová & E. Vavr̆iková, Curr. Pharm. Des. 2011, 17, 3596-3607), chitosan grafted with quaternary pyridinium (W. Sajomsang et al., Carbohydr. Polym. 2008, 72, 740-750), phosphonium and sulphonamide groups (Z. Zhong et al., Carbohydr. Res. 2008, 343, 566-570) have been reported for antimicrobial applications (Ö. V. Rúnarsson et al., Carbohydr. Res. 2008, 343, 2576-2582; and K. Kurita et al., Polym. J. 2007, 39, 945-952). However, the toxicities of such chitosan derivatives are still high due to the introduction of hydrophobic moieties together with cationic charges; the hydrophobic side groups also limit the application of the chitosan derivatives as antimicrobial agents in water due to reduced solubility. On the other hand, chitosan backbones tend to aggregate by formation of hydrogen bonds (K. Y. Lee et al., J. Control. Release 1998, 51, 213-220), and the aggregated chitosan nanoparticle without hydrophobic moieties functions as a cationic proton sponge, which can be used as an effective antimicrobial agent with high biocompatibility (Z. Hou et al., ACS Appl. Mater. Interfaces 2017, 9, 38288-38303). However, even though the antimicrobial effects of chitosan and its derivatives are well-reported, the efficacies are generally weak, making the bottleneck of real application of chitosan and its derivatives as antimicrobial agents (Z. Ma, A. Garrido-Maestu & K. C. Jeong, Carbohydr. Polym. 2017, 176, 257-265). Due to their unique membrane interruption ability (H. Liu et al., Int. J. Food Microbiol. 2004, 92, 147-155), cationic polysaccharides based on chitosan and its derivatives are good candidates to effectively sensitize the multi-drug resistant (MDR) bacteria to c