An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance

Abstract

Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens.

Carriage of Distinct mcr‐1‐Harboring Plasmids by Unusual Serotypes of Salmonella

“…Unfortunately, many species of Enterobacteriaceae are becoming increasingly resistant to colistin 2,4,6,7. One colistin resistant mechanism is the modification of Lipid A of LPS, catalyzed by the chromosome encoded machinery in Klebsiella pneumoniae , the LptA (EptA) in Neisseria , or mobile colistin resistance mcr‐1 in Enterobacteriaceae 5,8–11. Since its discovery in China, mcr‐1 resistance was reported in several other countries spanning six continents 5–7,12.…”

Antibiotic exposure elicits the emergence of colistin- and carbapenem-resistant Escherichia coli coharboring MCR-1 and NDM-5 in a patient

“…Unfortunately, it seems likely that the clinical use of carbapenems and colistin has been significantly challenged by the occurrence of mobilized colistin resistance determinant (MCR-1) in clinical carbapenem-resistant isolates producing New Delhi metallo- β -lactamase 1 (NDM-1) [6,7] or its variant NDM-5 [8,9]. In addition to the intrinsic determinants of colistin resistance (e.g., EptA [10,11] and ICR-Mo [12]), the transferable determinants (MCR-1 and MCR-2 [10,13,14]) consistently encode members of phosphoethanolamine (PEA)-lipid A transferases, which adopt a ‘ping-pong’ catalysis reaction in transferring of the PEA moiety to the 4ʹ-phosphate position of the lipopolysaccharide (LPS)-lipid A species anchored on bacterial surface [4,5]. …”

Non-clonal emergence of colistin resistance associated with mutations in the BasRS two-component system in Escherichia coli bloodstream isolates

“…also exclusively found phosphoethanolamine-modified lipid A in colistin-resistant clinical E. coli isolates (24). The reliance of Escherichia on the modification of lipid A by phosphoethanolamine to acquire colistin resistance, suggests that the inhibition of this class of enzymes by blocking the conserved catalytic site (31) could be a target for future drug development and opens the possibility of combination therapy with colistin and an inhibitor of phosphoethanolamine transferase (63). With the increasing clinical issues posed by infections with multidrug-resistant Gram-negative bacteria, there is an urgent need to better understand resistance mechanisms to last-resort antibiotics like colistin.…”