Department of Chemistry - PhD Student Seminar - Medicinal Chemistry Strategies Targeting the Outer Membrane Barrier of Gram-Negative Bacteria

Student: Ms. Xinwei ZHANG

Department: Department of Chemistry, HKUST

Supervisor: Prof. Rongbiao TONG

Abstract

This seminar examines medicinal chemistry strategies for overcoming the outer membrane (OM) barrier of Gram-negative bacteria—a primary driver of multidrug resistance. The asymmetric lipopolysaccharide (LPS) outer leaflet and size-restrictive porin channels impose conflicting physicochemical requirements on antibiotic entry, creating a fundamental design dilemma.

Classical small-molecule design, guided by the “eNTRy rules”, optimizes compounds for passive porin diffusion; however, this framework restricts the accessible chemical space. This seminar highlights frontier medicinal chemistry strategies that bypass these limitations through strategic target localization, specifically focusing on OM permeabilizers, Trojan horse conjugates, inhibitors of OM biosynthesis and assembly, and efflux pump inhibitors. By evaluating these medicinal chemistry strategies, this presentation illustrates how modern drug design can expand beyond the limitation to address the outer membrane barrier.