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Review
. 2016 Oct 3;6(10):a025288.
doi: 10.1101/cshperspect.a025288.

Polymyxin: Alternative Mechanisms of Action and Resistance

Affiliations
Review

Polymyxin: Alternative Mechanisms of Action and Resistance

Michael J Trimble et al. Cold Spring Harb Perspect Med. .

Abstract

Antibiotic resistance among pathogenic bacteria is an ever-increasing issue worldwide. Unfortunately, very little has been achieved in the pharmaceutical industry to combat this problem. This has led researchers and the medical field to revisit past drugs that were deemed too toxic for clinical use. In particular, the cyclic cationic peptides polymyxin B and colistin, which are specific for Gram-negative bacteria, have been used as "last resort" antimicrobials. Before the 1980s, these drugs were known for their renal and neural toxicities; however, new clinical practices and possibly improved manufacturing have made them safer to use. Previously suggested to primarily attack the membranes of Gram-negative bacteria and to not easily select for resistant mutants, recent research exploring resistance and mechanisms of action has provided new perspectives. This review focuses primarily on the proposed alternative mechanisms of action, known resistance mechanisms, and how these support the alternative mechanisms of action.

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Figures

Figure 1.
Figure 1.
The structure of polymyxin B and likely mode of membrane interaction. (A) The general structure of the cyclic cationic peptide polymyxin B. Colistin (polymyxin E) replaces the phenylalanine (d-Phe*) in polymyxin B with a leucine. Attenuated polymyxin nonapeptide has the fatty acyl tail removed adjacent to the threonine outside the ring structure (∼). (B) Polymyxin B interacts with the lipid A portion of the lipopolysaccharide (LPS) outer membrane. The peptides cross the outer membrane through a “self-promoted uptake” mechanism and then interact with the cytoplasmic membrane to inhibit cellular energization, and possibly cause inhibition of cell division and/or cytoplasmic membrane permeabilization and subsequent cell death.
Figure 2.
Figure 2.
General mechanisms of resistance to polymyxin by lipopolysaccharide (LPS) modifications in Salmonella (mechanisms differ in Pseudomonas). The two-component system PhoQP, activates expression of pmrD. PmrD activates PmrA, which activates cptA and the pmr and arn operons. Along with EptB, CptA modifies the LPS core. The products pmr and arn substitute the phosphates the lipid A portion of the LPS for PEtn and l-Ara4N, respectively. Collectively, the net charge of the outer membrane changes, resulting in repulsion of polymyxin.

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