Abstract
ABSTRACTCombinations 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.
Highlights
Combinations of antibiotics, each individually effective against Mycobacterium abscessus, are routinely coadministered based on the concept that this minimizes the spread of antibiotic resistance
We discovered a mechanism for antagonism between antibiotics currently used for M. abscessus therapy
Our studies revealed that clarithromycin, a bacteriostatic macrolide that is the cornerstone antibiotic for the treatment of M. abscessus infections, antagonized the activity of a partnered bactericidal aminoglycoside
Summary
Combinations of antibiotics, each individually effective against Mycobacterium abscessus, are routinely coadministered based on the concept that this minimizes the spread of antibiotic resistance. M. tuberculosis upregulates the expression of resistance genes [15, 18,19,20] able to combat internalized antibiotics These genes include eis (encoding an acetyltransferase that modifies aminoglycosides [18, 19, 21]), erm (encoding a ribosomal methyltransferase that prevents macrolide binding [22]), and tap (encoding an efflux pump able to export drugs, including aminoglycosides, tetracyclines, and para-aminosalicylic acid [23]). These genes all encode proteins that can provide resistance to certain antibiotics, increased expression is needed to optimize their activities. All of these resistance genes are upregulated by WhiB7, a transcriptional activator that is conserved across mycobacteria and related actinomycetes [18,19,20, 24]
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