PLoS computational biology, 2022-02, Vol.18 (2), p.e1009855-e1009855
2022
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- Autor(en) / Beteiligte
- Titel
- Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus
- Ist Teil von
- PLoS computational biology, 2022-02, Vol.18 (2), p.e1009855-e1009855
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2022
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) confers resistance to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this F98Y variant, yet this F98Y substitution still reduces efficacy of these agents. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of the NADPH cofactor. To understand the molecular basis of F98Y-mediated resistance and how PLAs' inhibition drives NADPH isomeric states, we used protein design algorithms in the osprey protein design software suite to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. Here, we present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs' inhibition, while other PLAs remain unaffected by this resistance mechanism.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7358, 1553-734XeISSN: 1553-7358DOI: 10.1371/journal.pcbi.1009855Titel-ID: cdi_plos_journals_2640120594
- Format
- –
- Schlagworte
- Algorithms, Antimicrobial agents, Antimicrobial resistance, Binding sites, Biology and Life Sciences, Catalysis, Chirality, Computer applications, Configurations, Dihydrofolate reductase, Drug resistance in microorganisms, Drug Resistance, Bacterial - genetics, Enzymes, Folic Acid Antagonists - chemistry, Folic Acid Antagonists - pharmacology, Health aspects, Health care, Humans, Medicine and Health Sciences, Microbiological research, Mutation, NADP - metabolism, Physical Sciences, Proteins, Reductases, Research and Analysis Methods, Software, Staphylococcal Infections, Staphylococcus aureus, Staphylococcus aureus - genetics, Staphylococcus aureus - metabolism, Staphylococcus infections, Tetrahydrofolate Dehydrogenase - chemistry, Tetrahydrofolate Dehydrogenase - genetics, Tetrahydrofolate Dehydrogenase - metabolism, Trimethoprim, Trimethoprim - chemistry, Trimethoprim - metabolism, Trimethoprim - pharmacology, Vitamin B