Role of efflux pumps, their inhibitors, and regulators in colistin resistance

Abstract

Colistin is highly promising against multidrug-resistant and extensively drug-resistant bacteria clinically. Bacteria are resistant to colistin mainly through mcr and chromosome-mediated lipopolysaccharide (LPS) synthesis-related locus variation. However, the current understanding cannot fully explain the resistance mechanism in mcr-negative colistin-resistant strains. Significantly, the contribution of efflux pumps to colistin resistance remains to be clarified. This review aims to discuss the contribution of efflux pumps and their related transcriptional regulators to colistin resistance in various bacteria and the reversal effect of efflux pump inhibitors on colistin resistance. Previous studies suggested a complex regulatory relationship between the efflux pumps and their transcriptional regulators and LPS synthesis, transport, and modification. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), 1-(1-naphthylmethyl)-piperazine (NMP), and Phe-Arg-β-naphthylamide (PAβN) all achieved the reversal of colistin resistance, highlighting the role of efflux pumps in colistin resistance and their potential for adjuvant development. The contribution of the efflux pumps to colistin resistance might also be related to specific genetic backgrounds. They can participate in colistin tolerance and heterogeneous resistance to affect the treatment efficacy of colistin. These findings help understand the development of resistance in mcr-negative colistin-resistant strains.

Synergistic action of 6-gingerol as an adjuvant to colistin for susceptibility enhancement in multidrug-resistant Klebsiella pneumoniae isolates

“…CCCP was then used as an efflux pump inhibitor to confirm efflux pump activity in colistin resistance isolates. 26 The MIC of CCCP was evaluated by broth microdilution method ranging from 128 to 0.5 μg mL −1 . The 1/2MIC of CCCP was used to investigate the presence of an efflux pump.…”

Colistin: Lights and Shadows of an Older Antibiotic

“…Addition of L-Ara4N and/or PEtn to lipidA changes the negative charge of the cell membrane by neutralizing the negatively charged phospholipids [47][48][49][50]. In detail, the addition of PEtn to the 1′-or 4′-phosphate group of lipid A is carried out by PmrC, a putative membrane protein with phosphoethanolamine transferase activity encoded by pmrABC operon [11,[51][52][53][54].…”

“…Further evidence for the role of efflux pumps in colistin resistance is the suppression of resistance by efflux pump inhibitor (EPI), cyanide-3-chlorophenylhydrazone (CCCP) in A. baumannii, P. aeruginosa, K. pneumoniae, and S. maltophilia [118]. However, a possible explanation is that CCCPmediated depolarization of the electrochemical gradient may restore the negative charge of the outer membrane and lead to increased susceptibility to colistin [48,118]. Furthermore, various studies suggested a complex regulatory relationship between the efflux pumps and their transcriptional regulators and LPS synthesis, transport, and modification [48].…”

“…However, a possible explanation is that CCCPmediated depolarization of the electrochemical gradient may restore the negative charge of the outer membrane and lead to increased susceptibility to colistin [48,118]. Furthermore, various studies suggested a complex regulatory relationship between the efflux pumps and their transcriptional regulators and LPS synthesis, transport, and modification [48].…”

Colistin: Lights and Shadows of an Older Antibiotic

“…The addition of L-Ara4N and/or PEtn to lipidA changes the negative charge of the cell membrane by neutralizing the negatively charged phospholipids [47][48][49][50]. In detail, the addition of PEtn to the 1′-or 4′-phosphate group of lipid A is carried out by PmrC, a putative membrane protein with phosphoethanolamine transferase activity encoded by pmrABC operons [11,[51][52][53][54].…”