TY - JOUR
T1 - Selection of antibiotic-resistant bacterial mutants
T2 - Allelic diversity among fluoroquinolone-resistant mutations
AU - Zhou, J.
AU - Dong, Y.
AU - Zhao, X.
AU - Lee, S.
AU - Amin, A.
AU - Ramaswamy, S.
AU - Domagala, J.
AU - Musser, James M.
AU - Drlica, K.
N1 - Funding Information:
Received 21 January 2000; revised 24 April 2000; electronically published 24 July 2000. Financial support: This work, which represents publication 73 from the Public Health Research Institute Tuberculosis Center, was supported by Public Health Service grants AI35257 (to K.D.) and AI37004 (to J.M.M.). aPresent affiliation: Cold Spring Harbor Laboratories, Cold Spring Harbor, New York. Reprints or correspondence: Dr. Karl Drlica, Public Health Research Institute, 455 First Ave., New York, NY 10016 (drlica@phri.nyu.edu).
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2000
Y1 - 2000
N2 - To obtain a general framework for understanding selection of antibiotic-resistant mutants, allelic diversity was examined with about 600 fluoroquinolone-resistant mutants of mycobacteria. Selection at low fluoroquinolone concentration produced many low-level resistance mutants. Some of these contained mutations that conferred unselected antibiotic resistance; none contained alterations in the quinolone-resistance-determining region of the GyrA protein, the principal drug target. As selection pressure increased, a variety of GyrA variants became prevalent. High concentrations of antibiotic reduced the variety to a few types, and eventually a concentration was reached at which no mutant was recovered. That concentration defined a threshold for preventing the selection of resistance. The pattern of variants selected, which was also strongly influenced by antibiotic structure, readily explained the variants present in clinical isolates. Thus, resistance arises from selection of mutants whose identity depends on drug concentration and structure, both of which can be manipulated to restrict selection.
AB - To obtain a general framework for understanding selection of antibiotic-resistant mutants, allelic diversity was examined with about 600 fluoroquinolone-resistant mutants of mycobacteria. Selection at low fluoroquinolone concentration produced many low-level resistance mutants. Some of these contained mutations that conferred unselected antibiotic resistance; none contained alterations in the quinolone-resistance-determining region of the GyrA protein, the principal drug target. As selection pressure increased, a variety of GyrA variants became prevalent. High concentrations of antibiotic reduced the variety to a few types, and eventually a concentration was reached at which no mutant was recovered. That concentration defined a threshold for preventing the selection of resistance. The pattern of variants selected, which was also strongly influenced by antibiotic structure, readily explained the variants present in clinical isolates. Thus, resistance arises from selection of mutants whose identity depends on drug concentration and structure, both of which can be manipulated to restrict selection.
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U2 - 10.1086/315708
DO - 10.1086/315708
M3 - Article
C2 - 10915083
AN - SCOPUS:0033836223
VL - 182
SP - 517
EP - 525
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 2
ER -