Biology subjects

Ojewole, A. A.

Publications and source records attributed to Ojewole, A. A..

2 recordsLinked to original sources

bioRxiv2020

Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus

Antimicrobial resistance is a health care crisis. The resistance-conferring mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) reduces effectiveness of antifolates, e.g., trimethoprim (TMP). Although propargyl-linked antifolates (PLAs) are much more resilient than TMP towards F98Y, this substitution still vitiates their inhibition potency. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of NADPH cofactor. Is resistance correlated with chiral evasion? A mechanism of action underpinning this coupling is unknown. To understand the molecular basis of F98Y-mediated resistance and how PLAs inhibition drives NADPH isomeric states, we used OSPREY to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. We present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs inhibition, while other PLAs remain resilient to resistance. Our model should enable general design of inhibitors that are resilient to chiral evasion.

biochemistry↗

bioRxiv2019

Toward Broad Spectrum DHFR inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin-Resistant Staphylococcus aureus

The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-confering isoforms. Using a structure-based approach, we have developed a novel class of ionized non-classical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMPR MRSA isolates.

biochemistry↗