Targeting bacterial metabolic pathways and lipid biogenesis to combat antimicrobial resistance

The global threat from antimicrobial resistance (AMR) was highlighted by the World Health Organization in its first-ever priority pathogen list of antibiotic-resistant bacteria. Indeed, AMR will cause an estimated 10 million deaths per year with a cumulative U$100 trillion economic impact by 2050, implying an urgent medical need for novel therapeutical options. Without new antibiotics, the old-class polymyxins including colistin and polymyxin B were reconsidered as a last-line therapy against multi-drug resistant (MDR) Gram-negative pathogens. Polymyxins target the lipid A component of lipopolysaccharide (LPS) and destabilise the Gram-negative outer membrane, following by the rupture and leakage of cytoplasmic contents; however, the precise mechanism of polymyxin killing remains unknown. Resistance to polymyxins is predominantly associated with the covalent modifications of lipid A with positively charged moieties, such as phosphoethanolamine (PEtN) and/or 4-amino-4-deoxy-L-arabinose (L-Ara4N), where are mediated by the respective transferases, EptA and ArnT. Notably, the recent emergence of plasmid-borne mcr-1 gene indicates that polymyxin resistance may readily spread. Therefore, it is crucial to understand the exact mechanism of polymyxin resistance in order to combat the growing threat of polymyxin-resistant ‘superbugs’. This research project integrates molecular biology, quantitative metabolomics and lipidomics (incl, stable isotope labelling), and metabolic modelling to study the metabolic pathways and lipid biogenesis responsible for polymyxin resistance, and how essential metabolites and lipids potentiate polymyxin killing against MDR bacterial isolates.