Abstract
The increased reliance on colistin for treating multidrug-resistant Gram-negative bacterial infections has resulted in the emergence of colistin-resistant Pseudomonas aeruginosa. We attempted to identify genetic contributors to colistin resistance in vitro evolved isogenic colistin-resistant and -susceptible strains of two P. aeruginosa lineages (P5 and P155). Their evolutionary paths to acquisition and loss of colistin resistance were also tracked. Comparative genomic analysis revealed 13 and five colistin resistance determinants in the P5 and P155 lineages, respectively. Lipid A in colistin-resistant mutants was modified through the addition of 4-amino-L-arabinose; this modification was absent in colistin-susceptible revertant strains. Many amino acid substitutions that emerged during the acquisition of colistin resistance were reversed in colistin-susceptible revertants. We demonstrated that evolved colistin resistance in P. aeruginosa was mediated by a complicated regulatory network that likely emerges through diverse genetic alterations. Colistin-resistant P. aeruginosa became susceptible to the colistin upon its withdrawal because of genetic reversion. The mechanisms through which P. aeruginosa acquires and loses colistin resistance have implications on the treatment options that can be applied against P. aeruginosa infections, with respect to improving bactericidal efficacy and preventing further resistance to antibiotics.
Highlights
The emergence and dissemination of antibiotic-resistant bacteria has had a profound influence on human and animal health and welfare, along with having economic consequences[1]
We previously obtained in vitro-selected colistin-resistant mutants from colistin-susceptible P. aeruginosa parental strains, P5 and P155, through repeated exposure to sub-inhibitory concentrations of colistin[30]
P5-4 and P155-4, intermediate strains selected in media with 4 mg/L colistin, showed markedly elevated colistin minimum inhibitory concentration (MIC), compared with intermediate strains selected in media with 2 mg/L colistin
Summary
The emergence and dissemination of antibiotic-resistant bacteria has had a profound influence on human and animal health and welfare, along with having economic consequences[1]. In contrast to intrinsic and acquired resistance mechanisms, which are stable and can be transmitted to progeny, adaptive resistance is transient and is usually lost upon removal of the antibiotic agent. This type of resistance has been reported for aminoglycosides and polymyxins (polymyxin B and colistin) in Pseudomonas aeruginosa and other Gram-negative bacilli[8,10,11,12]. Polymyxins bind to lipopolysaccharide (LPS), the major constituent of the outer membrane in Gram-negative bacteria, through interactions with phosphates and fatty acids of LPS core and lipid A moieties[13,14] These interactions subsequently result in cell lysis and death[15]. Increased use of polymyxins in therapy has resulted in the evolution of bacterial isolates with reduced susceptibility to this class of antibiotics worldwide[20,21,22]
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