Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria.

Abiola O Olaitan,Serge Morand,Jean-Marc Rolain

doi:10.3389/fmicb.2014.00643

Abstract

Polymyxins are polycationic antimicrobial peptides that are currently the last-resort antibiotics for the treatment of multidrug-resistant, Gram-negative bacterial infections. The reintroduction of polymyxins for antimicrobial therapy has been followed by an increase in reports of resistance among Gram-negative bacteria. Some bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, develop resistance to polymyxins in a process referred to as acquired resistance, whereas other bacteria, such as Proteus spp., Serratia spp., and Burkholderia spp., are naturally resistant to these drugs. Reports of polymyxin resistance in clinical isolates have recently increased, including acquired and intrinsically resistant pathogens. This increase is considered a serious issue, prompting concern due to the low number of currently available effective antibiotics. This review summarizes current knowledge concerning the different strategies bacteria employ to resist the activities of polymyxins. Gram-negative bacteria employ several strategies to protect themselves from polymyxin antibiotics (polymyxin B and colistin), including a variety of lipopolysaccharide (LPS) modifications, such as modifications of lipid A with phosphoethanolamine and 4-amino-4-deoxy-L-arabinose, in addition to the use of efflux pumps, the formation of capsules and overexpression of the outer membrane protein OprH, which are all effectively regulated at the molecular level. The increased understanding of these mechanisms is extremely vital and timely to facilitate studies of antimicrobial peptides and find new potential drugs targeting clinically relevant Gram-negative bacteria.

Highlights

Recently, the rise in infections caused by multidrug-resistant (MDR) Gram-negative bacteria, especially the resistance to carbapenems most importantly observed in Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, has led to the resuscitation of polymyxins worldwide as a last-resort treatment option (Stein and Raoult, 2002; Falagas and Michalopoulos, 2006; Biswas et al, 2012)
These strategies include alterations of their lipopolysaccharides (LPSs), which have overall negative charges and are the initial targets of polymyxins (Moffatt et al, 2010). Such alterations can be achieved by covalent modifications of the lipid A moiety of LPS through the addition of phosphoethanolamine (PEtN) and 4-amino-4-deoxy-L-arabinose (L-Ara4N), deacylation, hydroxylation and palmitoylation by pagP (Ernst et al, 2001; Raetz et al, 2007)
Resistance to polymyxin antibiotics depends on an intricate mechanism that involves several genes participating in bacterial cell membrane remodeling

Summary

Introduction

The rise in infections caused by multidrug-resistant (MDR) Gram-negative bacteria, especially the resistance to carbapenems most importantly observed in Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, has led to the resuscitation of polymyxins (polymyxin B and colistin) worldwide as a last-resort treatment option (Stein and Raoult, 2002; Falagas and Michalopoulos, 2006; Biswas et al, 2012). In polymyxin-resistant Salmonella, one principal mechanism underlying this modification, apart from external stimuli such as Mg2+, involves mutations in the PmrA/PmrB and PhoP/PhoQ TCSs. Mutations in these systems can cause their constitutive overexpression, resulting in the activation of the arnBCADTEF and pmrCAB operons and the modification of lipid A by L-Ara4N and PEtN, respectively (Figure 1) (Roland et al, 1993; Guo et al, 1997; Gunn et al, 1998; Zhou et al, 2001; Lee et al, 2004).

Results

Conclusion