Rifabutin Suppresses Inducible Clarithromycin Resistance in by Blocking Induction of and .

Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by . However, many strains harbor the CLR-inducible CLR resistance gene encoding a ribosome methylase. Induction of is mediated by the transcription factor . We hypothesized that an inhibitor of RNA synthesis should be able to block the induction response to CLR exposure and thus suppress CLR resistance. Recently, we discovered that the rifampicin analog rifabutin (RFB) shows attractive potency against . To determine whether RFB-CLR combinations are synergistic, a checkerboard analysis against a collection of positive and negative strains was carried out. This revealed synergy of the two drugs for positive but not for negative strains. To determine whether RFB's potentiation effect was due to inhibition of the transcriptional induction of the 7- resistance system, we measured the effect of CLR alone and in combination with RFB on and mRNA levels. CLR alone strongly induced and expression as expected. The synergistic, growth-inhibiting combination of RFB with CLR blocked induction of both genes. These results suggest that RFB suppresses inducible CLR resistance by preventing induction of 7 and expression.