Export by a quorum sensing-controlled drug exporter underlies rifampicin's strong activity against staphylococcal biofilms.

Abstract

Biofilm infections on indwelling medical devices are a major cause of health care-associated infection and mortality. Most of these infections are caused by staphylococci. Biofilm formation presents a continued clinical challenge because of the association with dramatically increased nonspecific antimicrobial resistance. Unlike most antibiotics, rifampicin is active against staphylococcal biofilm infections; however, the mechanism is unknown. Using in vitro assays and mouse models of biofilm infection, we show here that rifampicin is more effective than other antibiotics against staphylococcal <i>agr</i> mutants, which are linked to serious biofilm infections because they produce extended biofilms. We found that this superiority results from an Agr-controlled rifampicin efflux system, which makes <i>agr</i> mutant biofilms less resistant to rifampicin, rather than more resistant, than they are to other antibiotics. Our study provides a scientific rationale supporting the use of rifampicin in staphylococcal biofilm infections and emphasizes the importance of understanding genetic adaptations during infection for the use and development of biofilm therapeutics.