Selection of antibiotic-resistant bacterial mutants: allelic diversity among fluoroquinolone-resistant mutations.
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.
Public Health Research Institute, New York, New York 10016, USA.
J
J
Zhou
Y
Y
Dong
X
X
Zhao
S
S
Lee
A
A
Amin
S
S
Ramaswamy
J
J
Domagala
J M
JM
Musser
K
K
Drlica
D000483:Alleles; D000890:Anti-Infective Agents / Q000494:pharmacology*; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004352:Drug Resistance, Microbial / Q000235:genetics; D024841:Fluoroquinolones; D014644:Genetic Variation; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009161:Mycobacterium / Q000187:drug effects* / Q000235:genetics*; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012641:Selection, Genetic; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II