A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance 1 1 Edited by T.Richmond

Dale, Glenn E.; Broger, Clemens; D’Arcy, Allan; Hartman, P. G.; Dehoogt, R.; Jolidon, Synèse; Kompis, I.; Labhardt, Alexander M.; Langen, Hanno; Locher, Hans H.; Page, Malcolm G. P.; Stüber, Dietrich; Then, Rudolf L.; Wipf, Beat; Oefner, Christian

doi:10.1006/jmbi.1996.0770

Cited by 165 publications

(168 citation statements)

References 46 publications

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“…In order to elucidate the basis of its potency, we determined a crystal structure of the enzyme bound to its cofactor, NADPH and compound 1. Crystals of the wild-type Sa DHFR showed diffraction amplitudes to 2.1 Å (Table 1); the structure was determined with difference Fourier methods using coordinates of Sa (F98Y)DHFR (15). The model reveals the overall characteristic "DHFR fold" that consists of an eight-stranded beta sheet and four alpha helices connected by flexible loop regions.…”

Section: Resultsmentioning

confidence: 99%

“…For these searches, the algorithm used as input the crystal structure of Sa DHFR:compound 1∶NADPH as well as a model of Sa DHFR bound to NADPH and dihydrofolate, which was adapted from coordinates of a single mutant Sa DHFR bound to the same ligands (15). Ten active site residues (Leu 5, Val 6, Leu 20, Asp 27, Leu 28, Val 31, Thr 46, Ile 50, Leu 54, and Phe 92) were modeled as flexible using rotamers (16) and allowed to keep their wild-type identity or to mutate within a restricted group of amino acids (see Materials and Methods) that conserve the amino acid property or correlate with a different DHFR species.…”

Section: Resultsmentioning

confidence: 99%

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Predicting resistance mutations using protein design algorithms

Frey

Georgiev²,

Donald³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

115

155

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Drug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K Ã , to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance.negative design algorithm | DHFR | MRSA | K* design algorithm

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Predicting resistance mutations using protein design algorithms

Frey

Georgiev²,

Donald³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

115

155

View full text Add to dashboard Cite

show abstract

“…This has been found in S pneumoniae and H influenzae (279,280). TMP/SMX resistance in pneumococci is now very high.…”

Section: Tmp/smx Resistancementioning

confidence: 91%

Canadian Guidelines for the Management of Acute Exacerbations of Chronic Bronchitis

Balter

Forge

Low

et al. 2003

Canadian Respiratory Journal

116

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Acute exacerbations of chronic bronchitis (AECB) account for over 1.5 million physician visits annually in Canada and are a cause of significant morbidity and mortality. This document represents a joint effort between respirologists, microbiologists, infectious disease specialists and family physicians to update the Canadian AECB guidelines published in 1994. Treatment recommendations are graded on the strength of evidence in the published literature where possible. The role for oral corticosteroid therapy in preventing treatment failures, speeding up recovery and delaying the time to next exacerbation is discussed. Risk factors for treatment failure were used to stratify patients into risk groups to help guide antibiotic treatment recommendations. The importance of emerging antimicrobial resistance to current antibiotics is reviewed and strategies to prevent future AECB episodes are suggested.

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“…In Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Plasmodium falciparum, mutations in the DHFR genes were found to confer resistance to DHFR inhibitors including TMP and pyrimethamine [6][7][8][9][10]. Ma et al [11] have reported the cloning and sequencing of the DHFR gene in human-derived P. carinii.…”

Section: Introductionmentioning

confidence: 99%

Dihydrofolate reductase gene polymorphisms in Pneumocystis carinii f. sp. hominis in Japan

Takahashi¹,

Endo²,

Nakamura

et al. 2002

Journal of Medical Microbiology

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This study examined polymorphisms in the dihydrofolate reductase (DHFR) gene of Pneumocystis carinii isolates from 27 patients with P. carinii pneumonia (PCP) in Japan. Four substitution sites with two synonymous and two non-synonymous changes were found. Two synonymous substitutions at nucleotide positions 540 and 312 were identified in one and 13 patients, respectively. Two amino acid substitutions (Ala67Val, Cys166Tyr) were found in two different patients. No linkage of amino acid substitutions in DHFR to those in dihydropteroate synthase was observed. The two patients whose isolates showed non-synonymous DHFR mutations were not exposed to DHFR inhibitors before they developed PCP and were treated successfully with co-trimoxazole.

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A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance 1 1 Edited by T.Richmond

Cited by 165 publications

References 46 publications

Predicting resistance mutations using protein design algorithms

Predicting resistance mutations using protein design algorithms

Canadian Guidelines for the Management of Acute Exacerbations of Chronic Bronchitis

Dihydrofolate reductase gene polymorphisms in Pneumocystis carinii f. sp. hominis in Japan

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