Affiliation:
1. Department of Microbiology and Immunology and the Centre for Tuberculosis Research, University of British Columbia, Vancouver, Canada
Abstract
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.
Funder
Gouvernement du Canada | Canadian Institutes of Health Research
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
49 articles.
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