Export by a quorum sensing–controlled drug exporter underlies rifampicin’s strong activity against staphylococcal biofilms

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 agr 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 agr 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.