Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Poster Abstracts

1-POS Board 1 MODULATORY EFFECTS OF A QUINOLONE ALKALOID ON THE AMYLOIDOGENIC STRUCTURAL TRANSITIONS OF SMALL BASIC PROTEIN STRENGTHENING THE STAPHYLOCOCCAL BIOFILM MATRIX Nikita Admane 1 ; Sumit Biswas 1 ; Ram Kothandan 2 ; 1 BITS Pilani KK Birla Goa Campus, Department of Biological Sciences, Zuarinagar, India 2 Kumaraguru College of Technology, Coimbatore, India The spread of detrimental nosocomial and implant-associated infections is mainly attributed to the antibiotic-resistant bacterial biofilm formation by communities of opportunistic bacterial pathogens like Staphylococcus epidermidis. An 18-kDa small basic protein (Sbp) and its amyloid fibrils account for strengthening the biofilm architecture and scaffolding the S. epidermidis biofilm matrix, making it resistant to antibiotic treatment. Our study puts forward novel insights on the amyloidogenic structural transitions of Sbp and also reports amyloid core of the protein which may induce misfolding and aggregation. Herein, we describe the novel amyloid modulatory potential of Camptothecin (CPT), a quinoline alkaloid which binds stably to Sbp monomers. This heteromolecular association of Sbp with CPT further destabilizes the protein redirecting it towards unstructured aggregate formation. Molecular dynamics simulations reveal that Camptothecin interrupts with electrostatic interactions, averts β -sheet transitions and interrupts with the intermolecular hydrophobic associations between the exposed amyloidogenic hydrophobic cores of Sbp. Overall, this study presents the first report detailing the amyloid modulatory effects of Camptothecin which may serve as a structural scaffold for the tailored designing of novel drugs targeting the antibiotic resistant biofilm matrix of S. epidermidis. The findings of this study further warrant investigating the amyloid modulatory effects of other non toxic CPT analogues on Sbp aggregation. This will open new avenues for the rational discovery of non- toxic therapeutic agents targeting amyloid fibrils consolidating antibiotic resistant biofilm assembly on foreign body implants.

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