Smart Multifunctional Glycopolypeptides as Next-Generation Antibiotic Alternatives: Design, Mechanistic Insights and Strategies to Combat Antimicrobial Resistance

Das, Sabyasachi (2026) Smart Multifunctional Glycopolypeptides as Next-Generation Antibiotic Alternatives: Design, Mechanistic Insights and Strategies to Combat Antimicrobial Resistance. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Sabyasachi Das (19RS034)) 19RS034.pdf - Submitted Version Restricted to Repository staff only Download (19MB)

Abstract

The rapid emergence of antimicrobial resistance (AMR) has severely reduced the effectiveness of conventional antibiotics, creating an urgent need for advanced therapeutic strategies against persistent bacterial infections. Biofilm formation, intracellular bacterial survival, and multidrug resistance collectively hinder antibiotic penetration and therapeutic efficacy, necessitating multifunctional antimicrobial systems capable of targeted delivery and alternative antibacterial mechanisms. In this thesis, smart glycopolypeptide-based nanoplatforms were developed as next-generation antimicrobial therapeutics through rational molecular engineering, stimuli-responsive behaviour, and catalytic antibacterial strategies. A cationic α-helical glycopolypeptide–vancomycin conjugate was engineered to enhance intracellular antibiotic delivery, biofilm penetration, and bacterial targeting through guanidinium-mediated membrane interaction and mannose-directed cellular uptake, resulting in improved antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), efficient intracellular bacterial clearance, biofilm disruption, and accelerated wound healing. To achieve controlled and site-specific antibiotic release, stimuli-responsive cross-linked glycopolymersomes were developed as structurally stable nanocarriers capable of selective disassembly under acidic, reductive, and enzyme-rich infection microenvironments, thereby enabling enhanced biofilm infiltration and intracellular drug delivery. Furthermore, a supramolecular glycopolypeptide nanoplatform was designed for antibiotic-free antibacterial therapy. The ruthenium-integrated supra-amphiphilic nanoassemblies generated reactive oxygen and nitrogen species under visible-light irradiation and catalyzed NADH oxidation, leading to oxidative stress, metabolic disruption, and potent multimodal antibacterial activity. Overall, this thesis establishes multifunctional glycopolypeptide nanotherapeutics as versatile platforms for combating AMR, intracellular bacterial persistence, and biofilm-associated infections, while providing important mechanistic insights for advanced antimicrobial nanomedicine.

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