Combating antibiotic resistance: structural and biophysical studies of a colistin resistance enzyme involved in endotoxin modification

Vrielink A1, Anandan A1, Evans GL1, Condic-Jurkic K2, O’Mara ML2 and Kahler CM1

  1. University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009.
  2. The Australian National University, Canberra, ACT 2601.

Multiple drug resistance (MDR) in Gram-negative bacteria represents one of the most intractable problems facing modern medicine. Colistin and polymyxin are cationic antimicrobial peptide antibiotics which permeabilise the bacterial outer membrane and have been used to treat infections. Resistance to these antibiotics is conferred by the modification of the lipid A headgroups with phosphoethanolamine (PEA) moieties resulting in a reduced negative charge of the bacterial surface and exclusion of the drug. This modification is carried out by the enzyme, lipid A PEA transferase (EptA). Recently a mobile colistin resistance determinant, mcr-1, encoding an EptA homologue was identified in MDR Escherichia coli. The crystal structure of a full-length EptA from Neisseria sp. to 2.75Å resolution will be presented as well as molecular dynamics and biophysical studies. These studies help us to better understand the conformational flexibility of the protein and provide insights into the catalytic activity of the enzyme.