Abstract
Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by Mycobacterium abscessus (Mab). However, many strains harbor the CLR-inducible CLR resistance gene erm41, encoding a ribosome methylase. Induction of erm41 is mediated by the transcription factor whiB7. We hypothesized that an inhibitor of RNA synthesis should be able to block the whiB7–erm41 induction response to CLR exposure and thus suppress CLR resistance. Recently, we discovered that the rifampicin analog rifabutin (RFB) shows attractive potency against Mab. To determine whether RFB-CLR combinations are synergistic, a checkerboard analysis against a collection of erm41 positive and negative Mab strains was carried out. This revealed synergy of the two drugs for erm41 positive but not for erm41 negative strains. To determine whether RFB’s potentiation effect was due to inhibition of the transcriptional induction of the whiB7–erm41 resistance system, we measured the effect of CLR alone and in combination with RFB on whiB7 and erm41 mRNA levels. CLR alone strongly induced whiB7 and erm41 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 whiB7 and erm41 expression.
Highlights
Mycobacterium abscessus (Mab) causes difficult-to-cure lung disease
As predicted, the RFB-CLR combination was indifferent to all erm41 negative Mab strains, demonstrating that RFB
It is interesting to note that the outcomes of the drug–drug interaction studies were solely dependent on the erm41 status and not influenced by the type of subspecies
Summary
Mycobacterium abscessus (Mab) causes difficult-to-cure lung disease. Current multidrug-regimens typically include clarithromycin (CLR) (or its analog azithromycin), amikacin, imipenem and tigecycline [1,2,3]. The RNA polymerase inhibitor should block transcriptional induction of the whiB7-erm resistance system and hold the genotypically CLR resistant Mab in a phenotypically CLR susceptible state This hypothesis is supported by recent synergy studies that suggest that RFB can potentiate the activity of CLR [18,19]. We tested this hypothesis by determining the effect of RFB on CLR activity in erm positive and negative strains in vitro, and by determining the effect of RFB on transcript levels of whiB7 and erm
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