Polymyxin: Alternative Mechanisms of Action and Resistance

Trimble, Michael J.; Mlynárčik, Patrik; Kolář, Milan; Hancock, Robert E. W.

doi:10.1101/cshperspect.a025288

Cited by 330 publications

(347 citation statements)

References 215 publications

(233 reference statements)

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“…However, it is believed that activity is related, in part, to disruption of the bacterial outer and inner membranes via a ‘self-promoted uptake’ mechanism [13]. The initial step involves binding of the positively charged polymyxins to negatively charged lipopolysaccharide (LPS) on the outer membrane of Gram-negative bacteria both via electrostatic and hydrophobic interactions (Fig.…”

Section: Minimum Inhibitory Concentrations (Mics) and Mode Of Actionmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Tran

Velkov

Nation

et al. 2016

International Journal of Antimicrobial Agents

156

131

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The polymyxin antibiotics [colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available polymyxins have very different pharmacological properties, as colistin (polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the ‘bad bugs, no drugs’ era, polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative ‘superbugs’. Rational approaches to the use of polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.

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Section: Minimum Inhibitory Concentrations (Mics) and Mode Of Actionmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Tran

Velkov

Nation

et al. 2016

International Journal of Antimicrobial Agents

156

131

View full text Add to dashboard Cite

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“…A major reason for the renewal of interest in this drug was the belief that colistin resistance developed only through point mutation and was therefore not transmitted horizontally (2). This paradigm was recently upended with the discovery of the transferable colistin resistance gene mcr-1 (3).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Serial Isolates of mcr-1 -Positive Escherichia coli Reveals a Highly Active IS Apl1 Transposon

Snesrud

Ong

Corey

et al. 2017

Antimicrob Agents Chemother

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The emergence of a transferable colistin resistance gene (mcr-1) is of global concern. The insertion sequence ISApl1 is a key component in the mobilization of this gene, but its role remains poorly understood. Six Escherichia coli isolates were cultured from the same patient over the course of 1 month in Germany and the United States after a brief hospitalization in Bahrain for an unconnected illness. Four carried mcr-1 as determined by real-time PCR, but two were negative. Two additional mcr-1-negative E. coli isolates were collected during follow-up surveillance 9 months later. All isolates were analyzed by whole-genome sequencing (WGS). WGS revealed that the six initial isolates were composed of two distinct strains: an initial ST-617 E. coli strain harboring mcr-1 and a second, unrelated, mcr-1-negative ST-32 E. coli strain that emerged 2 weeks after hospitalization. Follow-up swabs taken 9 months later were negative for the ST-617 strain, but the mcr-1-negative ST-32 strain was still present. mcr-1 was associated with a single copy of ISApl1, located on a 64.5-kb IncI2 plasmid that shared >95% homology with other mcr-1 IncI2 plasmids. ISApl1 copy numbers ranged from 2 for the first isolate to 6 for the final isolate, but ISApl1 movement was independent of mcr-1. Some movement was accompanied by gene disruption, including the loss of genes encoding proteins involved in stress responses, arginine catabolism, and l-arabinose utilization. These data represent the first comprehensive analysis of ISApl1 movement in serial clinical isolates and reveal that, under certain conditions, ISApl1 is a highly active IS element whose movement may be detrimental to the host cell.

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“…Relying on electrostatic interaction, polymyxin can bind to the negatively charged cell surface, generated by LPS, of the gram‐negative bacteria. Polymyxin then inserts itself into the outer membrane, displacing the inner membrane (21, 22). There are different hypotheses to explain how polymyxin and other antimicrobial peptides kill microbes; some of which include the creation of physical holes that cause the cellular contents to leak and the fatal depolarization of the normally energized bacterial membrane (23, 24).…”

mentioning

confidence: 99%

Substrate analog interaction with MCR‐1 offers insight into the rising threat of the plasmid‐mediated transferable colistin resistance

et al. 2018

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Colistin is considered a last-resort antibiotic against most gram-negative bacteria. Recent discoveries of a plasmid-mediated, transferable mobilized colistin-resistance gene ( mcr-1) on all continents have heralded the imminent emergence of pan-drug-resistant superbacteria. The inner-membrane protein MCR-1 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in colistin resistance. However, little is known about the mechanism, and few drugs exist to address this issue. We present crystal structures revealing the MCR-1 catalytic domain (cMCR-1) as a monozinc metalloprotein with ethanolamine (ETA) and d-glucose, respectively, thus highlighting 2 possible substrate-binding pockets in the MCR-1-catalyzed PEA transfer reaction. Mutation of the residues involved in ETA and d-glucose binding impairs colistin resistance in recombinant Escherichia coli containing full-length MCR-1. Partial analogs of the substrate are used for cocrystallization with cMCR-1, providing valuable information about the family of PEA transferases. One of the analogs, ETA, causes clear inhibition of polymyxin B resistance, highlighting its potential for drug development. These data demonstrate the crucial role of the PEA- and lipid A-binding pockets and provide novel insights into the structure-based mechanisms, important drug-target hot spots, and a drug template for further drug development to combat the urgent, rising threat of MCR-1-mediated antibiotic resistance.-Wei, P., Song, G., Shi, M., Zhou, Y., Liu, Y., Lei, J., Chen, P., Yin, L. Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance.

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Polymyxin: Alternative Mechanisms of Action and Resistance

Cited by 330 publications

References 215 publications

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Analysis of Serial Isolates of mcr-1 -Positive Escherichia coli Reveals a Highly Active IS Apl1 Transposon

Substrate analog interaction with MCR‐1 offers insight into the rising threat of the plasmid‐mediated transferable colistin resistance

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