Chromosomally encoded and plasmid-mediated polymyxins resistance in Acinetobacter baumannii: a huge public health threat

Abstract

Acinetobacter baumannii is an opportunistic pathogen associated with nosocomial and community infections of great clinical relevance. Its ability to rapidly develop resistance to antimicrobials, especially carbapenems, has re-boosted the prescription and use of polymyxins. However, the emergence of strains resistant to these antimicrobials is becoming a critical issue in several regions of the world because very few of currently available antibiotics are effective in these cases. This review summarizes the most up-to-date knowledge about chromosomally encoded and plasmid-mediated polymyxins resistance in A. baumannii. Different mechanisms are employed by A. baumannii to overcome the antibacterial effects of polymyxins. Modification of the outer membrane through phosphoethanolamine addition, loss of lipopolysaccharide, symmetric rupture, metabolic changes affecting osmoprotective amino acids, and overexpression of efflux pumps are involved in this process. Several genetic elements modulate these mechanisms, but only three of them have been described so far in A. baumannii clinical isolates such as mutations in pmrCAB, lpxACD, and lpsB. Elucidation of genotypic profiles and resistance mechanisms are necessary for control and fight against resistance to polymyxins in A. baumannii, thereby protecting this class for future treatment.

Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019)

“…Different genes that encode the LPS-modifying enzymes include; i) the pmrCAB operon system that encodes for three functional proteins, namely; pEtN phosphotransferase PmrC (also known as eptA), the response regulator PmrA (also known as BasR), and the sensor kinase protein PmrB (also known as BasS). The function of the pEtN phosphotransferase PmrC is the addition of the cationic pEtN moiety to the lipid A of LPS [4,23,42].…”

“…PhoP/PhoQ and PmrA/PmrB TCSs both contain a sensor kinase; PhoQ and PmrB, respectively, which can senses the environmental signals, such as the reduction in cell envelope Mg +2 and Ca +2 contents and low pH, besides the presence of colistin, thus they can change the expression patterns of these TCSs [4,42].…”

“…Several studies have revealed that colistin-resistant A. baumannii isolates could change back into a susceptible phenotype through mutations in PmrA/B, which in turn, downregulates the operon PmrCAB expression [44][45][46]. Additionally, it has been reported that the partial removal of pmrC is associated with an increase in the susceptibility of colistin-resistant A. baumannii [42].…”

“…Additionally, lptD, lpsB, vacJ, and the locus of biotin synthesis, were identified in A. baumannii as contributors for polymyxins resistance. LptD (essential for the insertion of the newly synthesized LPS into the OM), was found implicated in polymyxins resistance in A. baumannii [42,48]. Bojkovic et al [48] reported that the removal of lptD results in the complete loss of LPS and reduction in polymyxin resistance in A. baumannii, whereas the lpsB gene protects A. baumannii from the bactericidal effect of colistin via encoding the glycosyltransferase that is responsible for the LPS synthesis [49].…”

“…Since polymyxins have an amphipathic nature and act likewise as other biological detergents, therefore, the efflux pump system may be involved in their resistance [42]. Commonly, the activation of these pumps results in an increase in resistance to different antibiotics concurrently, including colistin.…”