Peptide-based efflux pump inhibitors of the small multidrug resistance protein from Pseudomonas aeruginosa.

Peptide-based efflux pump inhibitors of the small multidrug resistance protein from Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2019 Jun 17;: Authors: Mitchell CJ, Stone TA, Deber CM Abstract Bacteria have acquired multiple mechanisms to evade the lethal effects of current therapeutics, hindering treatment of bacterial infections such as the pathogen P. aeruginosa, which is responsible for nosocomial and cystic fibrosis lung infections. One resistance mechanism involves membrane-embedded multidrug efflux pumps that can effectively extrude an array of substrates, including common antibiotics, dyes, and biocides. Among these is the small multidrug resistant (SMR) efflux protein, consisting of four transmembrane helices (TMs), that functions as an antiparallel dimer. TMs 1-3 comprise the substrate binding pocket, while TM4 contains a GG7 heptad sequence motif that mediates the SMR TM4-TM4 dimerization. In the present work, we synthesized a series of peptides containing the residues centered on the TM4-TM4 binding interface found in the P. aeruginosa SMR (PAsmr), typified by Ac-Ala-(Sar)3-LLGIGLIIAGVLV-KKK-NH2 (helix-helix interaction residues underlined). Here, the acetylated N-terminal sarcosine (N-methyl-Gly) tag promotes membrane penetration, while the C-terminal Lys tag promotes selectivity for the negatively-charged bacterial membranes. This peptide was observed to competitively disrupt PAsmr-mediated efflux, as measured b...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research