title: Rifalazil retains activity against rifampin-resistant mutants of Chlamydia pneumoniae.
abstract: Rifampin-resistant mutants of the obligate intracellular pathogen Chlamydia pneumoniae were isolated and characterized, including strains that contained multiple mutations in the rpoB gene encoding the rifampin binding site. The highest MIC of rifampin against a mutant strain exceeded 100 microg/ml, whereas the highest MIC of rifalazil was 0.125 microg/ml. Derivatives of rifalazil (new chemical entities; NCEs) showed from 2 approximately 4 fold lower MICs, as well as 2 approximately 8 fold lower bactericidal concentrations against both wild type and mutant strains when compared with rifalazil. These results suggest that rifalazil and NCEs are appropriate therapeutic agents for the treatment of C. pneumoniae infections from the point of view of potency and resistance development.
authors.affiliation: ActivBiotics, Inc, Lexington, MA, USA. drothstein@rcn.com
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Suchland
authors.forename: Minsheng
authors.initials: M
authors.lastname: Xia
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Murphy
authors.forename: Walter E
authors.initials: WE
authors.lastname: Stamm
mesh_terms: D000595:Amino Acid Sequence; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D023521:Chlamydophila Infections / Q000188:drug therapy / Q000382:microbiology; D016993:Chlamydophila pneumoniae / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D012293:Rifampin / Q000494:pharmacology*; D012294:Rifamycins / Q000494:pharmacology*; D016415:Sequence Alignment
chemical_list: D000904:Antibiotics, Antitubercular; D012294:Rifamycins; C068980:KRM 1648; D012293:Rifampin