Global epidemiology, genetic environment, risk factors and therapeutic prospects of mcr genes: A current and emerging update

Abstract

BackgroundMobile colistin resistance (mcr) genes modify Lipid A molecules of the lipopolysaccharide, changing the overall charge of the outer membrane.Results and discussionTen mcr genes have been described to date within eleven Enterobacteriaceae species, with Escherichia coli, Klebsiella pneumoniae, and Salmonella species being the most predominant. They are present worldwide in 72 countries, with animal specimens currently having the highest incidence, due to the use of colistin in poultry for promoting growth and treating intestinal infections. The wide dissemination of mcr from food animals to meat, manure, the environment, and wastewater samples has increased the risk of transmission to humans via foodborne and vector-borne routes. The stability and spread of mcr genes were mediated by mobile genetic elements such as the IncHI2 conjugative plasmid, which is associated with multiple mcr genes and other antibiotic resistance genes. The cost of acquiring mcr is reduced by compensatory adaptation mechanisms. MCR proteins are well conserved structurally and via enzymatic action. Thus, therapeutics found effective against MCR-1 should be tested against the remaining MCR proteins.ConclusionThe dissemination of mcr genes into the clinical setting, is threatening public health by limiting therapeutics options available. Combination therapies are a promising option for managing and treating colistin-resistant Enterobacteriaceae infections whilst reducing the toxic effects of colistin.

Genes mcr improve the intestinal fitness of pathogenic E. coli and balance their lifestyle to commensalism

“…The mcr family is rapidly growing and to date, 10 major lineages have been identified in Proteobacteria to date, such as E. coli , and encode proteins, which share 30–83% amino acid identity with mcr -1; a phophoethanolamine transferase domain, and the lipid A modification induced by Mcr-1 is seen across the different enzymes [ 38 ]. Each mcr gene is mostly located on conjugative plasmids widely distributed within Enterobacterale (e.g., E. coli and K. pneumoniae ) and they have also been reported within other Gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter spp [ 38 ]. We therefore investigated whether our observations were specific to mcr-1 or were a common trait shared by the mcr family.…”

Emergence of plasmid-mediated colistin resistance mcr-3.5 gene in Citrobacter amalonaticus and Citrobacter sedlakii isolated from healthy individual in Thailand

“…They are frequently isolated from E. coli , K. pneumoniae and Salmonella spp. ( Mmatli et al., 2022 ). In Thailand, various mcr alleles including mcr -1, mcr -2, mcr -3, mcr -6, mcr -7, mcr -8, and mcr -9 have been reported.…”

“…In Thailand, various mcr alleles including mcr -1, mcr -2, mcr -3, mcr -6, mcr -7, mcr -8, and mcr -9 have been reported. Most of these alleles were found to associate with farmed animals, especially pig and poultry ( Mmatli et al., 2022 ). Beside animals, prevalence of mcr -1 in human patients and co-occurrence of mcr -2 and mcr -3 on chromosome of multidrug-resistant Escherichia coli isolated from a healthy subject were recently reported by our group ( Eiamphungporn et al., 2018 ; Phuadraksa et al., 2022 ).…”

Strand-biased circularizing integrative elements spread tmexCD-toprJ gene clusters encoding RND-type multidrug efflux pumps by repeated transpositions

“…g. bla NDM , bla KPC , bla OXA-48-like , bla IMP , bla VIM , and bla GES-5-like ) (3), colistin resistance genes ( e . g. mcr and arnT ) (4, 5), and tigecycline resistance genes [ e . g. tet (X) and tmexCD-toprJ ] (6).…”

“…Carbapenem, colistin, and tigecycline are considered last-resort antimicrobials for infections caused by multidrug-resistant (MDR) gram-negative bacteria, such as Enterobacterales, Pseudomonas aeruginosa , and Acinetobacter baumannii , which are serious global public health threats (3, 4, 6). tet (X4) and other tet (X) variants, which encode flavin-dependent monooxygenases that catalyze tigecycline degradation, have emerged mainly in Enterobacterales and Acinetobacter species (3).…”