Phosphoethanolamine Transferases as Drug Discovery Targets for Therapeutic Treatment of Multi-Drug Resistant Pathogenic Gram-Negative Bacteria

Van C Thai; Keith A Stubbs; Mitali Sarkar-Tyson; Charlene M Kahler

doi:10.3390/antibiotics12091382

Phosphoethanolamine Transferases as Drug Discovery Targets for Therapeutic Treatment of Multi-Drug Resistant Pathogenic Gram-Negative Bacteria

Antibiotics (Basel). 2023 Aug 29;12(9):1382. doi: 10.3390/antibiotics12091382.

Authors

Van C Thai¹, Keith A Stubbs², Mitali Sarkar-Tyson¹, Charlene M Kahler¹

Affiliations

¹ The Marshall Center for Infectious Diseases Research and Training, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia.
² School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia.

Abstract

Antibiotic resistance caused by multidrug-resistant (MDR) bacteria is a major challenge to global public health. Polymyxins are increasingly being used as last-in-line antibiotics to treat MDR Gram-negative bacterial infections, but resistance development renders them ineffective for empirical therapy. The main mechanism that bacteria use to defend against polymyxins is to modify the lipid A headgroups of the outer membrane by adding phosphoethanolamine (PEA) moieties. In addition to lipid A modifying PEA transferases, Gram-negative bacteria possess PEA transferases that decorate proteins and glycans. This review provides a comprehensive overview of the function, structure, and mechanism of action of PEA transferases identified in pathogenic Gram-negative bacteria. It also summarizes the current drug development progress targeting this enzyme family, which could reverse antibiotic resistance to polymyxins to restore their utility in empiric therapy.

Keywords: EptA; Gram-negative bacteria; MCR; phosphoethanolamine transferases; polymyxin resistance.

Publication types

Review

Grants and funding

V.C.T. is supported by the University International Fee Scholarship (UIFS) and University Postgraduate Award (International Students) (UPAIS) from the University of Western Australia.