Recent progress on elucidating the molecular mechanism of plasmid-mediated colistin resistance and drug design

Abstract

Antibiotic resistance is a growing global challenge to public health. Polymyxin is considered to be the last-resort antibiotic against most gram-negative bacteria. Recently, discoveries of a plasmid-mediated, transferable mobilized polymyxin resistance gene ( mcr-1 ) in many countries have heralded the increased threat of the imminent emergence of pan-drug-resistant super bacteria. MCR-1 is an inner membrane protein that enables bacteria to develop resistance to polymyxin by transferring phosphoethanolamine to lipid A. However, the mechanism associated with polymyxin resistance has yet to be elucidated, and few drugs exist to address this issue. Here, we review our current understanding regarding MCR-1 and small molecule inhibitors to provide a detailed enzymatic mechanism of MCR-1 and the associated implications for drug design. Electronic supplementary material The online version of this article (10.1007/s10123-019-00112-1) contains supplementary material, which is available to authorized users.

Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin

“…Previous studies have shown that all the members of the MCR family proteins possess an identical secondary structure, with a high degree of conservation for the amino acid residues in the active site and PEA-interacting cavities. In particular, residues Glu246, Thr285, His390, Asp465, and His466 in the zinc-binding core and residues Asn108, Thr112, Glu116, Ser330, Lys333, His395, and His478 in the PEA binding cavity in MCR-1 are also located in similar positions in other MCR members 47 . Although there is no cysteine residues in the active site of MCR enzyme, to our surprise, unlike Bi(III) drugs, AUR also targets MCR-1 protein at its zinc-catalytic core through the side-chains (εN) of histidine residues, suggesting that the "softness" of histidine (e.g., εN) is tunable by a protein.…”

Vegetables and Fruit as a Reservoir of β-Lactam and Colistin-Resistant Gram-Negative Bacteria: A Review

“…The electrostatic interaction between the cationic region of colistin, which is from the diamino-butyric acid (Dab) residues, and the negatively charged phosphate groups of lipid A, replace the magnesium and calcium ions previously united with the phosphate group. This destabilizes the lipid A and increases the permeability of the outer membrane, leading to the entry of colistin by a self-promoted uptake mechanism and eventual bacterial death [26,29]. Another antibacterial mechanism is the inhibition of a crucial respiratory enzyme, the type II NADH-quinone oxidoreductase (NDH-2) in the bacterial cell membrane [29].…”

Total Synthesis of Novel Antimicrobial β-Hairpin Capitellacin Via Rapid Flow-Based SPPS Assembly and Regioselective On-Resin Disulfide Cyclisation

“…To date, a small number of AMPs have been successfully employed clinically (e.g. polymyxin B, colistin and daptomycin) to treat drug-resistant infections, although in many cases their application is limited by the toxicity of the native compounds (Barros et al 2019;Kai and Wang 2020;Poirel et al 2017;Yu et al 2015).…”