Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Tuesday Speaker Abstracts

MACROMOLECULE ENGINEERING APPROACH TO OVERCOMING ANTIMICROBIAL RESISTANCE Yiyan Yang 1 ; 1 Institute of Bioengineering and Bioimaging, Agency for Science, Technology and Research, Singapore, Singapore With the increased prevalence of antimicrobial resistance, there is an urgent need for development of innovative antimicrobial therapeutics. In this talk, biodegradable antimicrobial polymers, which are based on biodegradable guanidinium-functionalized polycarbonates or polypeptides, will be discussed. These polymers were synthesized via organocatalytic living ring-opening polymerization. This synthetic platform yields polymers/polypeptides with well defined molecular weight and structure, which allows for study of structure-activity relationship. We used confocal microscopy, SEM, TEM and bacterial RNA-Seq to study antimicrobial mechanism of the polymers. Unlike quaternary ammonium- or primary amine-functionalized polymers that killed bacteria via a membrane-disruption mechanism, the guanidinium functionalized polymers killed bacteria via membrane translocation followed by precipitation of intracellular proteins and genes. Bacterial RNA-Seq was also performed to study drug resistance development after repeated use of the polymers in comparison with small molecular antibiotics. Unlike antibiotics, multiple treatments using these polymers do not cause resistance. The synthetic macromolecules were engineered to fine tune hydrophobicity, hydrophilicity and structure for optimal antimicrobial activity and toxicity mitigation. The macromolecules with optimal compositions have strong activity against multidrug-resistant (MDR) bacteria without inducing significant toxicity. The optimized macromolecules demonstrated efficacy in an MRSA-infected skin wound infection mouse model. These macromolecular therapeutics hold potential for use in the treatment of MDR infection.

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