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Structural Mapping of Anion Inhibitors to β‐Carbonic Anhydrase psCA3 from Pseudomonas aeruginosa
ChemMedChem ( IF 3.4 ) Pub Date : 2018-09-13 , DOI: 10.1002/cmdc.201800375
Akilah B. Murray 1 , Mayank Aggarwal 2 , Melissa Pinard 3 , Daniela Vullo 4 , Marianna Patrauchan 5 , Claudiu T. Supuran 4 , Robert McKenna 1
Affiliation  

Pseudomonas aeruginosa is a Gram‐negative facultative anaerobe belonging to the Pseudomonadaceae family. It is a multidrug‐resistant opportunistic human pathogen, a common cause of life‐threatening nosocomial infections, and a key bacterial agent in cystic fibrosis and endocarditis. The bacterium exhibits intrinsic resistance to most antibacterial agents, including aminoglycosides and quinolones. Hence, the identification of new drug targets for P. aeruginosa is ongoing. PsCA3 is a β‐class carbonic anhydrase (β‐CA) that catalyzes the reversible hydration of carbon dioxide to bicarbonate and represents a new class of antimicrobial target. Previously, inhibitor screening studies of psCA3 have shown that a series of small anions including sulfamide (SFN), imidazole (IMD), and 4‐methylimidazole (4MI), and thiocyanate (SCN) inhibit the enzyme with efficiencies in the micro‐ to millimolar range. Herein the X‐ray crystal structures of these inhibitors in complex with psCA3 are presented and compared with human CA II. This structural survey into the binding modes of small anions forms the foundation for the development of inhibitors against β‐CAs and more selective inhibitors against P. aeruginosa.

中文翻译:

铜绿假单胞菌β-碳酸酐酶psCA3阴离子抑制剂的结构图

铜绿假单胞菌是革兰氏阴性兼性厌氧菌,属于假单胞菌科。它是一种多药耐药的机会性人类病原体,是威胁生命的医院感染的常见原因,并且是囊性纤维化和心内膜炎的关键细菌。该细菌对大多数抗菌剂(包括氨基糖苷类和喹诺酮类)表现出固有的抗性。因此,正在进行铜绿假单胞菌的新药物靶标的鉴定。PsCA3是一种β-类碳酸酐酶(β-CA),可催化二氧化碳可逆地水合成碳酸氢根,是一类新型的抗微生物靶标。以前,对psCA3的抑制剂筛选研究表明,一系列小阴离子包括磺酰胺(SFN),咪唑(IMD),4-甲基咪唑(4MI)和硫氰酸盐(SCN)抑制酶的效率在微摩尔至毫摩尔范围内。本文介绍了这些抑制剂与psCA3的X射线晶体结构,并将其与人CA II进行了比较。这种对小阴离子结合模式的结构研究为开发针对β-CAs的抑制剂和针对铜绿假单胞菌的更具选择性的抑制剂奠定了基础。
更新日期:2018-09-13
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