Antimicrob Agents Chemother. 2014; Apr 28.

Olivares Pacheco J, Alvarez-Ortega C, Martinez JL.

The acquisition of antibiotic resistance has been associated to a possible non-specific, metabolic burden that is reflected in a decrease in fitness among resistant bacteria. We have recently demonstrated that overexpression of the MexEF-OprN multi drug efflux pump does not produce a metabolic burden when measured by classical competitions tests but rather leads to a number of changes in the organism's physiology.

One of these changes is the untimely activation of the nitrate respiratory chain in aerobic conditions. MexEF-OprN is a proton/substrate antiporter. Overexpression of this element should result in a constant influx of protons that may lead to cytoplasmic acidification. Acidification was not observed in aerobiosis, a situation in which the MexEF-overproducing mutant increases oxygen consumption. This enhanced oxygen uptake serves to eliminate intracellular proton accumulation preventing a cytoplasmic acidification that was observed exclusively in anaerobic conditions, a situation in which the fitness of the MexEF-OprN overproducing mutant decreases. Finally, we determined that early activation of the nitrate respiratory chain in aerobic conditions plays a role in preventing a deleterious effect associated with overexpression of MexEF-OprN.

Our results show that metabolic rewiring may assist in overcoming the potential fitness cost associated with the acquisition of antibiotic resistance. Furthermore, the capability to metabolically compensate this effect is habitat-dependent, as demonstrated by our results in anaerobic conditions. The development of drugs that prevent metabolic compensation of fitness costs may help to reduce the persistence and dissemination of antibiotic resistance.