Targeting Lipopolysaccharides for the Development of LPS-Binding Potentiators

Abstract

The rise of Gram-negative pathogens that are resistant to all currently known antibiotics threatens to create a public health crisis. Gram-negative bacteria, by possessing an outer membrane, are resistant to many classes of antibiotics. Compounds that bind lipopolysaccharides (LPS) at the outer membrane, and permeabilize the cell to those otherwise impermeable antibiotics are termed ‘potentiators’. Those LPS-binding potentiators could be used in the clinic as antibiotic adjuvants to help combat Gram-negative resistance. In this project, the LPS-binding characteristics of potentiators are studied. Pentamidine, is a recently discovered LPS-binding potentiator. This work quantifies pentamidine’s affinity to LPS and suggests approaches to achieve higher affinity. This knowledge could lead to the development of safer, more effective potentiators. Additionally, this project uncovers currently commercially available drugs for their LPS-binding ability. We discovered that LPS-binding is not a sole predictor of potentiation ability. However, those compounds could be a starting point for the development of novel potentiators. Moreover, in this work, we study the interaction of polymyxins with lipopolysaccharides under mobile colistin resistance (mcr-1) conditions. We highlight that, while the mcr-1 mechanism of resistance is complex, the ability of polymyxins to interact with lipopolysaccharides and permeabilize the cell persists. This makes the development and exploitation of potentiators as tools for treating highly drug-resistant Gram-negative infections of great importance.