6MH4

Crystal Structure of 1-deoxy-D-xylulose-5-phosphate reductoisomerase from Staphylococcus schleiferi, Apoenzyme

6MH4 の概要

• エントリーDOI: 10.2210/pdb6mh4/pdb
• 分子名称: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, SULFATE ION (3 entities in total)
• 機能のキーワード: reductoisomerase, staphylococci, mep pathway, fosmidomycin, glpt, oxidoreductase
• 由来する生物種: Staphylococcus schleiferi
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85169.29

構造登録者

Lee, S.G.,Jez, J.M. (登録日: 2018-09-17, 公開日: 2020-03-18, 最終更新日: 2024-03-13)

主引用文献

Edwards, R.L.,Heueck, I.,Lee, S.G.,Shah, I.T.,Miller, J.J.,Jezewski, A.J.,Mikati, M.O.,Wang, X.,Brothers, R.C.,Heidel, K.M.,Osbourn, D.M.,Burnham, C.D.,Alvarez, S.,Fritz, S.A.,Dowd, C.S.,Jez, J.M.,Odom John, A.R.
Potent, specific MEPicides for treatment of zoonotic staphylococci.
Plos Pathog., 16:e1007806-e1007806, 2020

PubMed Abstract: Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.

PubMed: 32497104
DOI: 10.1371/journal.ppat.1007806

実験手法

X-RAY DIFFRACTION (2.15 Å)