Rifampin-resistant RNA polymerase mutants of Chlamydia trachomatis remain susceptible to the ansamycin rifalazil.
Stable, homotypic mutants of Chlamydia trachomatis for which MICs of rifampin and rifalazil are elevated were isolated by serial passage at sub-MIC concentrations of these compounds. An alternative approach, in which Chlamydia cells were incubated and subsequently passaged three times, all in the presence of the selective agent at concentrations above the MIC, appeared to be a more effective means of selecting for mutants. In every instance where an elevation in the MIC occurred, one or more mutations in the rpoB gene, encoding the rifampin binding site, were detected. With one exception, all rpoB mutants that contained a single mutation conferred lower levels of resistance than mutants containing multiple mutations. Some rpoB mutations conferred very high levels of resistance to rifampin, up to 512 mug/ml. In all cases, mutants remained susceptible to concentrations of rifalazil at or below 0.064 microg/ml. Thus, rifalazil, a compound that is extremely potent against Chlamydia wild-type cells (MIC of 0.00025 microg/ml), may also protect against the selection of mutants at physiologically achievable concentrations.
Suchland
Robert J
RJ
Department of Internal Medicine, University of Washington, Seattle, Washington, USA.
Bourillon
Agnès
A
Denamur
Erick
E
Stamm
Walter E
WE
Rothstein
David M
DM
D002692:Chlamydia trachomatis / Q000187:drug effects*; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D024881:Drug Resistance, Bacterial; D005838:Genotype; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D012293:Rifampin / Q000494:pharmacology*; D012294:Rifamycins / Q000494:pharmacology*
D012294:Rifamycins; C068980:KRM 1648; D012321:DNA-Directed RNA Polymerases; C105078:RNA polymerase beta subunit; D012293:Rifampin
Antimicrob Agents Chemother. 1999 Nov;43(11):2813-6
10543773
J Antimicrob Chemother. 1998 Nov;42(5):621-8
9848446
Antimicrob Agents Chemother. 2001 Feb;45(2):532-9
11158751
J Antimicrob Chemother. 2001 Feb;47(2):153-6
11157898
Cell. 2001 Mar 23;104(6):901-12
11290327
Antimicrob Agents Chemother. 2001 Jul;45(7):1972-6
11408210
Int J Tuberc Lung Dis. 2002 Feb;6(2):166-70
11931418
Antimicrob Agents Chemother. 2003 Feb;47(2):636-42
12543671
Expert Opin Investig Drugs. 2003 Feb;12(2):255-71
12556219
Antimicrob Agents Chemother. 2003 Mar;47(3):1135-6
12604555
Antimicrob Agents Chemother. 2003 Jul;47(7):2316-8
12821487
Clin Pharmacokinet. 2003;42(9):819-50
12882588
Rev Infect Dis. 1983 Jul-Aug;5 Suppl 3:S562-4
6635446
Antimicrob Agents Chemother. 1994 May;38(5):1118-22
8067748
Antimicrob Agents Chemother. 1996 Nov;40(11):2655-7
8913484
Antimicrob Agents Chemother. 1998 Jul;42(7):1853-7
9661035
J Infect Dis. 2000 Sep;182(3):909-16
10950788