Antagonism between Front-Line Antibiotics Clarithromycin and Amikacin in the Treatment of Mycobacterium abscessus Infections Is Mediated by the <i>whiB7</i> Gene

Abstract

Combinations of antibiotics, each individually effective against <i>Mycobacterium abscessus</i>, are routinely coadministered based on the concept that this minimizes the spread of antibiotic resistance. However, our <i>in vitro</i> data contradict this assumption and instead document antagonistic interactions between two antibiotics (clarithromycin and amikacin) used to treat <i>M. abscessus</i> infections. Clinically relevant concentrations of clarithromycin induced increased resistance to both amikacin and itself. The induction of resistance was dependent on <i>whiB7</i>, a transcriptional activator of intrinsic antibiotic resistance that is induced by exposure to many different antibiotics. In <i>M. abscessus</i>, the deletion of <i>whiB7</i> (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-<i>M. abscessus</i> drugs: clarithromycin, amikacin, and tigecycline. The <i>whiB7</i>-dependent gene that conferred macrolide resistance was identified as <i>erm</i>(41) (MAB_2297), which encodes a ribosomal methyltransferase. The <i>whiB7</i>-dependent gene contributing to amikacin resistance was <i>eis2</i> (MAB_4532c), which encodes a Gcn5-related <i>N</i>-acetyltransferase (GNAT). Transcription of <i>whiB7</i> and the resistance genes in its regulon was inducible by subinhibitory concentrations of clarithromycin but not by amikacin. Thus, exposure to clarithromycin, or likely any <i>whiB7</i>-inducing antibiotic, may antagonize the activities of amikacin and other drugs. This has important implications for the management of <i>M. abscessus</i> infections, both in cystic fibrosis (CF) and non-CF patients.