6P9Z

Staphylococcus aureus Dihydrofolate reductase in complex with NADPH and Methotrexate

6P9Z の概要

• エントリーDOI: 10.2210/pdb6p9z/pdb
• 分子名称: Dihydrofolate reductase, METHOTREXATE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: dhfr, methotrexate, antifolate, nadph, antimicrobial protein, oxidoreductase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19305.49

構造登録者

Reeve, S.M.,Wright, D.L. (登録日: 2019-06-10, 公開日: 2019-10-23, 最終更新日: 2023-10-11)

主引用文献

Reeve, S.M.,Si, D.,Krucinska, J.,Yan, Y.,Viswanathan, K.,Wang, S.,Holt, G.T.,Frenkel, M.S.,Ojewole, A.A.,Estrada, A.,Agabiti, S.S.,Alverson, J.B.,Gibson, N.D.,Priestley, N.D.,Wiemer, A.J.,Donald, B.R.,Wright, D.L.
Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin ResistantStaphylococcus aureus.
Acs Infect Dis., 5:1896-1906, 2019

PubMed Abstract: The spread of plasmid borne resistance enzymes in clinical 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-conferring isoforms. Using a structure-based approach, we have developed a novel class of ionized nonclassical 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 TMP resistant (TMP) and methicillin resistant (MRSA) isolates.

PubMed: 31565920
DOI: 10.1021/acsinfecdis.9b00222

実験手法

X-RAY DIFFRACTION (1.86 Å)