How might bacteria respond to agents like efflux pump inhibitors

Due to evolutionary selection pressures, antimicrobial agents have the propensity to trigger development of resistance in bacteria. Hence targeting resistance mechanisms, like inhibiting efflux transporters that extrude drugs,is typically undertaken. It would be interesting to see how bacteria would respond to these efflux inhibitors.

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Efflux pump inhibitors (EPI) act by inhibiting drug efflux in bacteria, thereby increasing intracellular drug concentration which would facilitate resensitization of bacteria to same old drugs to which it showed resistance. But from the bacterial perspective, how would it respond to these EPI's?

One predictable response would be that they overexpress related pumps that might transport same drug. This might work because these pumps display broad substrate specificity, whereas among EPI, not the ones like CCCP but at least certain EPI like PABN might exhibit narrow specificity. In gram negatives, if the inhibitors are also large hydrophobic molecules they might be regulated by porins.

The question is: can the efflux inhibitor of one pump (say pump A) be expelled by the other pump (pump B)?Will they really work in a biofilm context? There are a very few reports on effect of EPI against biofilms. One report from Prof. Piddock's lab (Baugh et al., 2013) shows that in Salmonella spp, Efflux transporter knock out mutants/ standard efflux pump inhibitors, rather than inhibiting the transport of biofilm specific factor, alters the expression of curli genes leading to inhibition of biofilm formation. Infact, this could be a side effect rather than direct effect of EPI in a biofilm context.

Could there be other responses like the ones that we see for antibiotics? After all it appears that we might need multi-pronged approach to tackle MDR bacteria

Saisubramanian Nagarajan

Assistant Professor,