Affiliation:
1. Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA
2. School of Public Health, University at Albany, Albany, New York, USA
Abstract
ABSTRACT
Tetracyclines have been one of the most successful classes of antibiotics. However, its extensive use has led to the emergence of widespread drug resistance, resulting in discontinuation of use against several bacterial infections. Prominent resistance mechanisms include drug efflux and the use of ribosome protection proteins. Infrequently, tetracyclines can be inactivated by the TetX class of enzymes, also referred to as tetracycline destructases. Low levels of tolerance to tetracycline in
Mycobacterium smegmatis
and
Mycobacterium tuberculosis
have been previously attributed to the WhiB7-dependent TetV/Tap efflux pump. However,
Mycobacterium abscessus
is ∼500-fold more resistant to tetracycline than
M. smegmatis
and
M. tuberculosis
. In this report, we show that this high level of resistance to tetracycline and doxycycline in
M. abscessus
is conferred by a WhiB7-independent tetracycline-inactivating monooxygenase, MabTetX (MAB_1496c). The presence of sublethal doses of tetracycline and doxycycline results in a >200-fold induction of MabTetX, and an isogenic deletion strain is highly sensitive to both antibiotics. Further, purified MabTetX can rapidly monooxygenate both antibiotics. We also demonstrate that expression of MabTetX is repressed by MabTetR
x
, by binding to an inverted repeat sequence upstream of MabTetR
x
; the presence of either antibiotic relieves this repression. Moreover, anhydrotetracycline (ATc) can effectively inhibit MabTetX activity
in vitro
and decreases the MICs of both tetracycline and doxycycline
in vivo
. Finally, we show that tigecycline, a glycylcycline tetracycline, not only is a poor substrate of MabTetX but also is incapable of inducing the expression of MabTetX. This is therefore the first demonstration of a tetracycline-inactivating enzyme in mycobacteria. It (i) elucidates the mechanism of tetracycline resistance in
M. abscessus
, (ii) demonstrates the use of an inhibitor that can potentially reclaim the use of tetracycline and doxycycline, and (iii) identifies two sequential bottlenecks—MabTetX and MabTetR
x
—for acquiring resistance to tigecycline, thereby reiterating its use against
M. abscessus
.
Funder
New York Community Trust
New York State Department of Health
New York State Department of Health-Wadsworth Center
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
52 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献