the effect of the overexpression of efflux pumps on bacterial fitness, as well as the effect of loss of efflux function on virulence
The acquisition of drug resistance is associated with a fitness cost for bacteria; overexpression of efflux pumps could decrease fitness by increasing energy consumption, as well as the constant extrusion of metabolites that are required for growth. However, studies have shown that Pseudomonas aeruginosa cells that overexpress the resistance-nodulation-division (RND) multidrug resistance MexEF–OprN efflux pump do not exhibit a decrease in fitness, and that the expression of genes that are involved in the nitrate respiratory chain was increased, which suggests that mutant cells adapt their metabolic pathways to compensate for a possible loss in fitness. Olivares-Pacheco et al. determined whether this 'metabolic rewiring' is a general mechanism in antibiotic-resistant P. aeruginosa cells that overexpress RDN efflux pumps. Indeed, mutants that overexpressed MexAB–OprM, MexCD–OprJ or MexXY exhibited increased expression of genes that are involved in the nitrate respiratory chain, as well as an increase in the consumption of nitrate and the production of nitric oxide. Moreover, these mutant cells also consumed more oxygen than the wild type, which suggests that both increased anaerobic and aerobic respiration are required to compensate for fitness costs. The activity of overexpressed RND pumps might also increase the intracellular proton concentration. The authors propose that cells might increase aerobic respiration to eliminate excess protons and restore pH homeostasis. In agreement with this, all mutants had a decreased intracellular pH under oxygen-limiting conditions. Similarly, limiting nitrate in the growth medium resulted in growth impairment in mutant cells. These findings suggest that the overexpression of RND efflux pumps results in intracellular acidification. In mutant cells, oxygen consumption increases, which restores the physiological pH but depletes intracellular oxygen levels. In response to oxygen-limited conditions, cells might induce alternative energy generation pathways, such as the nitrate respiratory chain, to metabolically compensate for fitness costs.
This is a preview of subscription content, access via your institution
