Chiral Evasion and Stereospecific Antifolate Resistance in Staphylococcus Aureus

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2022 Feb 10

PMID 35143481

Authors

Siyu Wang

Stephanie M Reeve

Graham T Holt

Adegoke A Ojewole

Marcel S Frenkel

Pablo Gainza

Santosh Keshipeddy

Vance G Fowler

Dennis L Wright

Bruce R Donald

Affiliations

Soon will be listed here.

Abstract

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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References

Case D, Cheatham 3rd T, Darden T, Gohlke H, Luo R, Merz Jr K . The Amber biomolecular simulation programs. J Comput Chem. 2005; 26(16):1668-88. PMC: 1989667. DOI: 10.1002/jcc.20290. View

Georgiev I, Lilien R, Donald B . The minimized dead-end elimination criterion and its application to protein redesign in a hybrid scoring and search algorithm for computing partition functions over molecular ensembles. J Comput Chem. 2008; 29(10):1527-42. PMC: 3263346. DOI: 10.1002/jcc.20909. View

Leach A, Lemon A . Exploring the conformational space of protein side chains using dead-end elimination and the A* algorithm. Proteins. 1998; 33(2):227-39. DOI: 10.1002/(sici)1097-0134(19981101)33:2<227::aid-prot7>3.0.co;2-f. View

Klemm A, Steiner T, Cumme G, Horn A . Determination, purification, and characterization of alpha-NADH. Anal Biochem. 1993; 212(2):375-80. DOI: 10.1006/abio.1993.1343. View

Gronenborn A, Birdsall B, Hyde E, Roberts G, Feeney J, Burgen A . 1H and 31P NMR characterization of two conformations of the trimethoprim-NADP+-dihydrofolate reductase complex. Mol Pharmacol. 1981; 20(1):145-53. View

Keshipeddy S, Reeve S, Anderson A, Wright D . Nonracemic Antifolates Stereoselectively Recruit Alternate Cofactors and Overcome Resistance in S. aureus. J Am Chem Soc. 2015; 137(28):8983-90. PMC: 4733634. DOI: 10.1021/jacs.5b01442. View

Bystroff C, Oatley S, KRAUT J . Crystal structures of Escherichia coli dihydrofolate reductase: the NADP+ holoenzyme and the folate.NADP+ ternary complex. Substrate binding and a model for the transition state. Biochemistry. 1990; 29(13):3263-77. DOI: 10.1021/bi00465a018. View

Visentin M, Zhao R, Goldman I . The antifolates. Hematol Oncol Clin North Am. 2012; 26(3):629-48, ix. PMC: 3777421. DOI: 10.1016/j.hoc.2012.02.002. View

Gainza P, Roberts K, Donald B . Protein design using continuous rotamers. PLoS Comput Biol. 2012; 8(1):e1002335. PMC: 3257257. DOI: 10.1371/journal.pcbi.1002335. View

10.

Dale G, Broger C, Darcy A, Hartman P, DeHoogt R, Jolidon S . A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. J Mol Biol. 1997; 266(1):23-30. DOI: 10.1006/jmbi.1996.0770. View

11.

Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P . Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol. 2003; 10(5):357-65. DOI: 10.1038/nsb921. View

12.

Schnell J, Dyson H, Wright P . Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct. 2004; 33:119-40. DOI: 10.1146/annurev.biophys.33.110502.133613. View

13.

Suzuki S, Suzuki K, Imai T, Suzuki N, Okuda S . ISOLATION OF ALPHA-PYRIDINE NUCLEOTIDES FROM AZOTOBACTER VINELANDII. J Biol Chem. 1965; 240:PC554-6. View

14.

Stover P . One-carbon metabolism-genome interactions in folate-associated pathologies. J Nutr. 2009; 139(12):2402-5. PMC: 2777484. DOI: 10.3945/jn.109.113670. View

15.

Gainza P, Nisonoff H, Donald B . Algorithms for protein design. Curr Opin Struct Biol. 2016; 39:16-26. PMC: 5065368. DOI: 10.1016/j.sbi.2016.03.006. View

16.

Reeve S, Gainza P, Frey K, Georgiev I, Donald B, Anderson A . Protein design algorithms predict viable resistance to an experimental antifolate. Proc Natl Acad Sci U S A. 2015; 112(3):749-54. PMC: 4311853. DOI: 10.1073/pnas.1411548112. View

17.

Hallen M, Martin J, Ojewole A, Jou J, Lowegard A, Frenkel M . OSPREY 3.0: Open-source protein redesign for you, with powerful new features. J Comput Chem. 2018; 39(30):2494-2507. PMC: 6391056. DOI: 10.1002/jcc.25522. View

18.

Lilien R, Stevens B, Anderson A, Donald B . A novel ensemble-based scoring and search algorithm for protein redesign and its application to modify the substrate specificity of the gramicidin synthetase a phenylalanine adenylation enzyme. J Comput Biol. 2005; 12(6):740-61. DOI: 10.1089/cmb.2005.12.740. View

19.

Frei C, Miller M, Lewis 2nd J, Lawson K, Hunter J, Oramasionwu C . Trimethoprim-sulfamethoxazole or clindamycin for community-associated MRSA (CA-MRSA) skin infections. J Am Board Fam Med. 2010; 23(6):714-9. DOI: 10.3122/jabfm.2010.06.090270. View

20.

Chen C, Georgiev I, Anderson A, Donald B . Computational structure-based redesign of enzyme activity. Proc Natl Acad Sci U S A. 2009; 106(10):3764-9. PMC: 2645347. DOI: 10.1073/pnas.0900266106. View