Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria

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.

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

“…In Gram-negative bacteria, lipid A in the outer membrane is the substrate for various positively charged modifications. Biosynthesis pathways for these modifications are not shown (For details see [116-118]). In certain species of both Gram-positive and Gram-negative bacteria, aminoacyl-phosphatidylglycerol synthases (aaPGSs) transfer aa from aa-tRNA (pre-formed by cytosolic aa-tRNA synthetases, aaRS) to phosphatidylglycerol (PG) in the membrane.…”

Increased colistin resistance upon acquisition of the plasmid-mediated mcr-1 gene in Escherichia coli isolates with chromosomally encoded reduced susceptibility to polymyxins

“…The emergence of chromosomal mutations in genes involved in the modification of lipopolysaccharide, e.g. in pmrAB, is responsible for colistin resistance [1,2]. However, the major source of concern is related to the recent discovery of plasmid-mediated colistin resistance genes (mcr-1 to -3) owing to the risk of spread of colistin resistance [2,3].…”

The whole genome sequencing of Acinetobacter-calcoaceticus-baumannii complex strains involved in suspected outbreak in an Intensive Care Unit of a pediatric hospital

“…It is to be stressed that blaOXA-23 gene encodes the most prevalent and endemic carbapenemase in Italy. [41] Regarding the analysis of polymixins, all the strains analyzed had a phenotypic susceptibility that correlate with the absence of a specific genetic determinant except PmrB-P170L [26,28] in ST195 strain, that in a single report was indicated as responsible for a possible resistant mechanism. [16] In general, our genetic data confirmed the phenotypic susceptibility test objectively supporting the antibiotic therapies adopted by clinicians.…”

“…To analyze the genes responsible for Polymyxins resistance we investigated the presence of mutations in PmrA, PmrB and the lpxA, lpxC, lpxD genes. [26][27][28][29][30][31] Acinetobacter baumannii strains characterized by ST281, ST195, ST744 do not present any mutations for the PmrA, lpxA, lpxC genes. The analysis of PmrB gene showed that the ST281 presented 3 mutations (P188T, N440H, A444V), the ST744 had 2 mutations (L237M, N440H) and finally the ST195 displayed 3 mutations (P170L, N440H, A444V).…”