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Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.

Publication ,  Journal Article
Wang, S; Reeve, SM; Holt, GT; Ojewole, AA; Frenkel, MS; Gainza, P; Keshipeddy, S; Fowler, VG; Wright, DL; Donald, BR
Published in: PLoS Comput Biol
February 2022

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.

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Published In

PLoS Comput Biol

DOI

EISSN

1553-7358

Publication Date

February 2022

Volume

18

Issue

2

Start / End Page

e1009855

Location

United States

Related Subject Headings

  • Trimethoprim
  • Tetrahydrofolate Dehydrogenase
  • Staphylococcus aureus
  • Staphylococcal Infections
  • NADP
  • Humans
  • Folic Acid Antagonists
  • Drug Resistance, Bacterial
  • Bioinformatics
  • 08 Information and Computing Sciences
 

Citation

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Wang, S., Reeve, S. M., Holt, G. T., Ojewole, A. A., Frenkel, M. S., Gainza, P., … Donald, B. R. (2022). Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus. PLoS Comput Biol, 18(2), e1009855. https://doi.org/10.1371/journal.pcbi.1009855
Wang, Siyu, Stephanie M. Reeve, Graham T. Holt, Adegoke A. Ojewole, Marcel S. Frenkel, Pablo Gainza, Santosh Keshipeddy, Vance G. Fowler, Dennis L. Wright, and Bruce R. Donald. “Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.PLoS Comput Biol 18, no. 2 (February 2022): e1009855. https://doi.org/10.1371/journal.pcbi.1009855.
Wang S, Reeve SM, Holt GT, Ojewole AA, Frenkel MS, Gainza P, et al. Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus. PLoS Comput Biol. 2022 Feb;18(2):e1009855.
Wang, Siyu, et al. “Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.PLoS Comput Biol, vol. 18, no. 2, Feb. 2022, p. e1009855. Pubmed, doi:10.1371/journal.pcbi.1009855.
Wang S, Reeve SM, Holt GT, Ojewole AA, Frenkel MS, Gainza P, Keshipeddy S, Fowler VG, Wright DL, Donald BR. Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus. PLoS Comput Biol. 2022 Feb;18(2):e1009855.

Published In

PLoS Comput Biol

DOI

EISSN

1553-7358

Publication Date

February 2022

Volume

18

Issue

2

Start / End Page

e1009855

Location

United States

Related Subject Headings

  • Trimethoprim
  • Tetrahydrofolate Dehydrogenase
  • Staphylococcus aureus
  • Staphylococcal Infections
  • NADP
  • Humans
  • Folic Acid Antagonists
  • Drug Resistance, Bacterial
  • Bioinformatics
  • 08 Information and Computing Sciences