Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus

• DOI: 10.1021/acsinfecdis.9b00222
• Publication Date: 2019-10-01T02:56:16Z
• Authors: Stephanie M. Reeve; Debjani Si; Jolanta Krucinska; Yongzhao Yan; Kishore Viswanathan; Siyu Wang; Graham T. Holt; Marcel S. Frenkel; Adegoke A. Ojewole; Alexavier Estrada; Sherry S. Agabiti; Jeremy B. Alverson; Nathan D. Gibson; Nigel D. Priestley; Andrew J. Wiemer; Bruce R. Donald; Dennis L. Wright
• Keywords: Dihydrofolate reductase; Trimethoprim; Antifolate

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