Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
07
07
2021
accepted:
21
01
2022
revised:
23
02
2022
pubmed:
11
2
2022
medline:
13
4
2022
entrez:
10
2
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35143481
doi: 10.1371/journal.pcbi.1009855
pii: PCOMPBIOL-D-21-01260
pmc: PMC8865654
doi:
Substances chimiques
Folic Acid Antagonists
0
NADP
53-59-8
Trimethoprim
AN164J8Y0X
Tetrahydrofolate Dehydrogenase
EC 1.5.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009855Subventions
Organisme : NIAID NIH HHS
ID : R01 AI111957
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM078031
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM118543
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM144042
Pays : United States
Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests: B.R.D. and M.S.F. are founders of Ten63 Therapeutics. V.G.F. reports personal fees (consultancy) from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J. V.G.F. has grants received or pending to his institution from following entities: NIH, MedImmune, Cerexa, Forest, Actavis, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, Janssen. V.G.F. received educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, Debiopharm. V.G.F. received royalties from UpToDate. V.G.F. has a pending patent on host gene expression signature diagnostic for sepsis. B.R.D. was previously a guest editor for PLoS Comp. Biol.
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