title: Sequence polymorphisms in the Pneumocystis carinii cytochrome b gene and their association with atovaquone prophylaxis failure.
abstract: Atovaquone (Mepron, 566c80) is an effective agent against Pneumocystis carinii, which probably acts by binding to cytochrome b and inhibiting electron transport. To assess the possibility that atovaquone resistance might be developing, the genes for the cytochrome b from P. carinii sp. f. carinii and P. carinii sp. f. hominis were partially sequenced. Eight of 10 patient isolates had cytochrome b genes with the same amino acid sequence. The P. carinii cytochrome b genes from 2 of 4 patients who had atovaquone prophylaxis failure contained mutations resulting in amino acid changes in one of the ubiquinone (coenzyme Q) binding sites (Qo). These mutations are homologous to mutations in other microorganisms that confer resistance to similar inhibitors. Variations in the sequence of the P. carinii cytochrome b gene suggest but do not prove the development of drug resistance.
authors.affiliation: Department of Epidemiology, Division of Infectious Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Walker
authors.forename: A E
authors.initials: AE
authors.lastname: Wakefield
authors.forename: M N
authors.initials: MN
authors.lastname: Dohn
authors.forename: R F
authors.initials: RF
authors.lastname: Miller
authors.forename: R P
authors.initials: RP
authors.lastname: Baughman
authors.forename: P A
authors.initials: PA
authors.lastname: Hossler
authors.forename: M S
authors.initials: MS
authors.lastname: Bartlett
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Kazanjian
authors.forename: S R
authors.initials: SR
authors.lastname: Meshnick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D053626:Atovaquone; D003573:Cytochrome b Group / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D019143:Evolution, Molecular; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D009285:Naphthoquinones / Q000627:therapeutic use*; D010802:Phylogeny; D011010:Pneumocystis / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011485:Protein Binding; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D017211:Treatment Failure
chemical_list: D000935:Antifungal Agents; D003573:Cytochrome b Group; D017931:DNA Primers; D009285:Naphthoquinones; D053626:Atovaquone