The growing number of antibiotic-resistant bacterial infections, combined with the decline of new antibiotic drug approvals, has created a therapeutic gap that leads to the emerging public health crisis. In search of alternates for antibiotics, synthetic mimics of antimicrobial peptides (SMAMPs) in the form of antimicrobial polymers have gained tremendous attention in the biomedical field. Here, we report the synthesis and mechanism of random amphiphilic methacrylamide based antibiotic polymers that mimic membrane-active cationic AMPs. The mole fraction of hydrophobic/hydrophilic groups were systematically varied to explore the structural parameters that influenced polymers activity and selectivity and allowed us to obtain an optimum composition of polymers suitable to act as non-toxic antimicrobials. The chemical structure and composition of copolymers were characterized by 1H NMR spectroscopy. The antibacterial activity was evaluated by determining minimum inhibitory concentration (MIC) against gram-positive S. aureus and gram-negative E .coli, while toxicity to mammalian cells was quantified by hemolysis assay with human red blood cells (RBCs). The antibacterial activity and selectivity of synthesized polymers depend on the mole fraction of aromatic benzyl units (fbenzyl) and the average molecular weight (Mn). Polymers with fbenzyl of 0.10 & 0.19, named AB-10 and AB-19, exhibited the highest antibacterial efficacy without inducing hemolysis and were chosen for further study. Live/dead membrane viability assay confirmed the bactericidal nature of the polymers. Liposome dye leakage study and observations from confocal and scanning electron microscopy indicate that the AB polymers killed bacterial cells primarily by disrupting the cytoplasmic membrane. Thirty days serial passage study with AB-19 polymer failed to generate resistance mutants of E. coli and S. aureus. These results are highly promising in the current scenario where multi-drug resistant pathogens challenge our ability to treat infectious diseases.

Methacrylamide based antibiotic polymers with no detectable bacterial resistance

ACS Spring Meeting 2021

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