Antagonism between front line antibiotics clarithromycin and amikacin used for the treatment of Mycobacterium abscessus infections is mediated by the whiB7 gene [PublishAheadOfPrint]

Combinations of antibiotics, each individually effective against Mycobacterium abscessus, are routinely co-administered based on the concept that this minimizes the spread of antibiotic resistance. However, our in vitro data contradicts this assumption and instead documents antagonistic interactions between two antibiotics (clarithromycin and amikacin) used to treat M. abscessus infections. Clinically relevant concentrations of clarithromycin induced increased resistance to both amikacin and itself. Induction of resistance was dependent on whiB7, a transcriptional activator of intrinsic antibiotic resistance that is induced by exposure to many different antibiotics. In M. abscessus, deletion of whiB7 (MAB_3508c) resulted in increased sensitivity to a broad range of antibiotics. WhiB7 was required for transcriptional activation of genes that confer resistance to three commonly used anti-M. abscessus drugs: clarithromycin, amikacin, and tigecycline. The whiB7-dependent gene that conferred macrolide resistance was identified as erm(41) (MAB_2297), a ribosomal methyltransferase. The whiB7-dependent gene contributing to amikacin resistance was eis2 (MAB_4532c), a GNAT acetyl transferase. Transcription of whiB7 and resistance genes in its regulon was inducible by subinhibitory concentrations of clarithromycin but not by amikacin. Thus, exposure to clarithromycin, or likely any whiB7-inducing antibiotic, may antagonize the activity of amikacin and other drugs. This has important implications for management of M. abscessus infections, both in cystic fibrosis (CF) and non-CF patients.

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