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.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is one of leading causes of healthcare associated infections, pneumonia and skin and soft tissue infections (SSTIs)
We compared to the literature [40,41,42,43] reports of an NMR study of an alternative Nicotinamide adenine dinucleotide phosphate (NADPH) complexed with Lactobacillus casei dihydrofolate reductase (DHFR)
We showed that incubation with both tautomer of NADPH (t-NADPH) and R-27 results in an approximately two-fold decrease in IC50 compared to incubation with R-27 alone (Fig E in S1 Text)
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is one of leading causes of healthcare associated infections, pneumonia and skin and soft tissue infections (SSTIs). Antifolates such as trimethoprim (TMP) exhibit potent activity as antibacterial agents against many MRSA clinical isolates [1, 2]. NADPH participates as a cofactor and donates a hydride to reduce C4 on the dihydropterin ring of DHF. NADPH adds a hydride to C6 of the dihydropterin ring and N5 is protonated [6, 9]. In Escherichia coli DHFR, Tyr stabilizes the positive charge in the nicotinamide ring during the hydride transfer between C4 of the nicotinamide ring and C6 of the dihydropterin ring [10]. Its mutation to tyrosine confers resistance to antifolates such as TMP and some other novel antifolates according to experimental and clinical observations [11, 12]
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