8‐Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase. Issue 8 (9th January 2018)

• Record Type: Journal Article
• Authors: Dennis, Matthew L.; Lee, Michael D.; Harjani, Jitendra R.; Ahmed, Mohamed; DeBono, Aaron J.; Pitcher, Noel P.; Wang, Zhong‐Chang; Chhabra, Sandeep; Barlow, Nicholas; Rahmani, Raphaël; Cleary, Ben; Dolezal, Olan; Hattarki, Meghan; Aurelio, Luigi; Shonberg, Jeremy; Graham, Bim; Peat, Thomas S.; Baell, Jonathan B.; Swarbrick, James D.
• Is Part Of: Chemistry. Volume 24:Issue 8(2018)
• Page Start: 1922
• Page End: 1930
• Publication Date: 2018-01-09
• Subjects: antibiotics -- DHPS -- drug discovery -- inhibitors -- pterin -- substrate-envelope hypothesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201704730
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7, 8‐dihydropteroate (DHPt) from 6‐hydroxymethyl‐7, 8‐dihydropterin pyrophosphate (DHPPP) and para ‐aminobenzoic acid (pABA). DHPS is the long‐standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild‐type and sulfa drug resistant strains. Following the work on developing pterin‐site inhibitors of the adjacent enzyme 6‐hydroxymethyl‐7, 8‐dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8‐mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub‐μm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand‐bound EcDHPS crystal structures delineate the structure–activity relationship observed providing a structural framework for the rational development of novel, substrate‐envelope‐compliant DHPS inhibitors. Abstract : Within the envelope : Structure‐based evolution of the 8‐mercaptoguanine fragment leads to tight binding, substrate‐envelope‐compliant derivatives that occupy the pterin‐site of the antibiotic target DHPS.