Linked Life Data

15770087

Source:http://linkedlifedata.com/resource/pubmed/id/15770087

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2005-3-16
pubmed:abstractText
Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP). Drug treatment failure has been associated epidemiologically with point mutations in the gene for dihydropteroate synthase which is part of a gene that encodes three covalently linked enzymes involved in folic acid synthesis (FAS). The evaluation of whether mutations found in P. jirovecii FAS lead to sulfa drug resistance is hampered by the lack of a culture system for P. jirovecii as well as the failure of P. jirovecii FAS to complement in a heterologous system. Therefore, we chose to model the P. jirovecii mutations in the Saccharomyces cerevisiae FAS protein (encoded by FOL1) via its expression in Escherichia coli. An optimized drug diffusion assay was used to evaluate the FAS mutants against 15 sulfa drugs. It was established that the single amino acid substitution, P599S, in the (DHPS) domain of FAS led to sulfa drug resistance, whereas the T597A substitution led to increased sensitivity. The presence of both mutations (T597A and P599S) was cooperative and led to increased sulfa drug resistance. Analysis of a novel double mutant, (T597V P599S) was found to have significantly higher sulfa drug resistance than the T597A P599S mutant. These data suggest that further amino acid substitutions may lead to the evolution of higher sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine and sulfathiazole) were identified that had higher inhibitory potential than sulfamethoxazole, which is currently the preferred treatment for PCP.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1076-6294
pubmed:author
pubmed:issnType
Print
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1-8
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Analysis of Pneumocystis jirovecii DHPS alleles implicated in sulfamethoxazole resistance using an Escherichia coli model system.
pubmed:affiliation
CSIRO Health Sciences and Nutrition, Parkville, Victoria, 3052, Australia. peter.iliades@csiro.au
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.