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

Abstract

Combinations of antibiotics, each individually effective against Mycobacterium abscessus, are routinely coadministered based on the concept that this minimizes the spread of antibiotic resistance. However, our in vitro data contradict this assumption and instead document 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. The 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, the 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), which encodes a ribosomal methyltransferase. The whiB7-dependent gene contributing to amikacin resistance was eis2 (MAB_4532c), which encodes a Gcn5-related N-acetyltransferase (GNAT). Transcription of whiB7 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 whiB7-inducing antibiotic, may antagonize the activities of amikacin and other drugs. This has important implications for the management of M. abscessus infections, both in cystic fibrosis (CF) and non-CF patients.

• Authors: Mark Pryjma, Ján Burian, Kevin Kuchinski, Charles J Thompson
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 61 Issue 11 (11 2017) ISSN: 1098-6596 [Electronic] United States
• PMID: 28874379 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Pryjma et al.

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Amikacin
• Clarithromycin

Topics

• Amikacin (antagonists & inhibitors, pharmacology)
• Anti-Bacterial Agents (pharmacology)
• Bacterial Proteins (genetics)
• Clarithromycin (pharmacology)
• Drug Antagonism
• Drug Resistance, Multiple, Bacterial (drug effects, genetics)
• Gene Expression Regulation, Bacterial
• Humans
• Microbial Sensitivity Tests
• Mycobacterium Infections, Nontuberculous (drug therapy, microbiology)
• Mycobacterium abscessus (drug effects, genetics, isolation & purification)