Pterin-sulfa conjugates as dihydropteroate synthase inhibitors and antibacterial agents

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Zhao, Ying¹  Shadrick, William R.¹  Wallace, Miranda J.¹  Wu, Yinan^3,4  Griffith, Elizabeth C.³  Qi, Jianjun²  Yun, Mi-Kyung³  White, Stephen W.^3,4  Lee, Richard E.^1,2 

[1] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 262 Danny Thomas Pl,Mail Stop 1000, Memphis, TN 38105 USA

[2] Univ Tennessee, Hlth Sci Ctr, Dept Pharmaceut Sci, Memphis, TN 38163 USA

[3] St Jude Childrens Res Hosp, Dept Biol Struct, 262 Danny Thomas Pl,Mail Stop 311, Memphis, TN 38105 USA

[4] Univ Tennessee, Hlth Sci Ctr, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA

关键词: Sulfonamide;    Antibiotics;    Antifolate;    Dihydropteroate synthase;    Pterin;   

DOI  :  10.1016/j.bmcl.2016.07.006

来源: Elsevier

【 摘 要 】

The sulfonamide class of antibiotics has been in continuous use for over 70 years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin-sulfonamide conjugates. In this study, eight pterin-sulfonamide conjugates were synthesized using a novel synthetic strategy and their biochemical and microbiological properties were investigated. The conjugates were shown to competitively inhibit DHPS, and inhibition was enhanced by the presence of pyrophosphate that is crucial to catalysis and is known to promote an ordering of the DHPS active site. The co-crystal structure of Yersinia pestis DHPS bound to one of the more potent conjugates revealed a mode of binding that is similar to that of the enzymatic product analog pteroic acid. The antimicrobial activities of the pterin-sulfonamide conjugates were measured against Escherichia coli in the presence and absence of folate precursors and dependent metabolites. These results show that the conjugates have appreciable antibacterial activity and act by an on target, anti-folate pathway mechanism rather than as simple dead end products. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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