A comparative investigation of the permeability of small molecules and antimicrobial peptides in phospholipid and lipopolysaccharide membranes

• Grant number: 25/03260-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Thereza Amélia Soares da Silva
• Grantee: Mariana Yoshinaga
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 22/07231-7 - Plasticity and functional modulation of intrinsically disordered proteins, AP.TEM

Abstract

Antimicrobial resistance (AMR) poses a major global health threat, with 1.27 million deaths reported in 2019 and projections of 10 million by 2050. In Gram-negative bacteria, the outer membrane (OM) made of lipopolysaccharides (LPS) acts as a barrier that limits antibiotic uptake. A key challenge in developing effective antibiotics is the lack of understanding of how cell envelope components regulate permeability. Existing experimental studies are limited by the oversimplification of membrane models, with phospholipid-only based models often used to mimic LPS OM, failing to capture its full complexity. In this project, we propose to compare the permeability of small molecules and antimicrobial peptides in phospholipid-only and LPS membrane models, considering the complexity of high-charge systems, using free energy calculation computational methods. This study will provide insights into how membrane components affect antibiotic penetration and enhance our understanding of drug-membrane interactions in Gram-negative bacteria. Since altered membrane permeability is a well-known bacterial resistance mechanism, understanding these interactions is crucial for the development of more effective antibiotics. (AU)