Polymers as advanced antibacterial and antibiofilm agents for direct and combination therapies

Abstract

The growing prevalence of antimicrobial drug resistance in pathogenic bacteria is a critical threat to global health. Conventional antibiotics still play a crucial role in treating bacterial infections, but the emergence and spread of antibiotic-resistant micro-organisms are rapidly eroding their usefulness. Cationic polymers, which target bacterial membranes, are thought to be the last frontier in antibacterial development. This class of molecules possesses several advantages including a low propensity for emergence of resistance and rapid bactericidal effect. This review surveys the structure-activity of advanced antimicrobial cationic polymers, including poly(α-amino acids), β-peptides, polycarbonates, star polymers and main-chain cationic polymers, with low toxicity and high selectivity to potentially become useful for real applications. Their uses as potentiating adjuvants to overcome bacterial membrane-related resistance mechanisms and as antibiofilm agents are also covered. The review is intended to provide valuable information for design and development of cationic polymers as antimicrobial and antibiofilm agents for translational applications.

Fig. 1. (a) Chemical structure of anionic molecules in bacterial envelopes. (b) Chemical structures of cytoplasmic lipids in bacteria and mammalian cells.

Scheme 1. Synthetic schemes to prepare cationic polymers.

Fig. 2. Chemical structures of cationic antimicrobial (a) poly(α-amino acids), (b) β-peptides, and (c) polycarbonates.

Fig. 3. Chemical structures of cationic antimicrobial (a) star polymers, (b) main-chain cationic polymers and (c) phosphonium polymers. (a(1) adapted from ref. with permission from Springer Nature, copyright (2016); a(3) adapted from ref. with permission from American Chemical Society, copyright (2016)).

Fig. 4. (a) Bacterial membrane-related intrinsic resistance mechanisms (left) and combination therapy with outer membrane permeabilizers and efflux pump inhibitors (right) (adapted from ref. with permission from John Wiley and Sons, copyright (2020)). (b) Chemical structures of outer membrane permeabilizers and efflux pump inhibitors: (1) beta-peptide PAS8-b-PDM12, (2) amino acid conjugated polymer ACP, (3) hydrophilic cationic polyurethane, (4) vitamin E-containing cationic polycarbonate, (5) amphiphilic ternary copolymer, (6) chitosan derivative (2,6-DAC) and (7) cationic lipo-peptide C12_(ω7) K-β₁₂.

Fig. 5. (a) Cartoon representation of biofilm formation and biofilm structure. (b) Chemical structures of antibiofilm polymers: (1) chitosan derivative, (2) and (3) polymethacrylate, (4) amphiphilic ternary copolymer, (5) polysaccharide-based amphiphilic ternary copolymer DA₉₅B₅, (6) main-chain cationic polycarbonate 8 M PDEA MeI, (7) guanidinium functionalized pillar[5]arene GP5, (8) cationic peptidomimetic Gly-POX, (9) peptoid HS(Naeg)₂₀ and (10) beta-peptide PDGu(7)-b-PBLK(13).

Fig. 6. Smart responsive antibacterial systems triggered by (a) pH, (b) enzymes and (c) bacterial surface anionic charge. ((a) adapted from ref. with permission from the Royal Society of Chemistry under the terms and conditions of the Creative Commons Attribution License; (b) adapted from ref. with permission from American Chemical Society, copyright (2012); (c) adapted from ref. with permission from American Chemical Society, copyright (2021)).

Fig. 7. Chemical structures and cartoon schemes illustrating pH-triggered antimicrobial polymers ((1) adapted from ref. with permission from National Academy of Sciences, copyright (2017)).

Fig. 8. Chemical structures and cartoon schemes illustrating (a) enzyme-triggered antimicrobial polymers and (b) bacterial membrane charge-triggered antimicrobial polymers. (a(2) adapted from ref. with permission from John Wiley and Sons, copyright (2017); b(2) adapted from ref. with permission from American Chemical Society, copyright (2021)).