Mechanism and Potential Inhibitors of GlmU: A Novel Target for Antimicrobial Drug Discovery

Author(s): Rashmi Sharma, Inshad Ali Khan*.

Journal Name: Current Drug Targets

Volume 18 , Issue 14 , 2017

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Abstract:

Background: Multidrug resistant Gram negative pathogens pose a persistent threat to the health care system and require investigation of new targets and molecules for the development of antibiotics to treat infections caused by MDR bacterial pathogens.

Objective: It is essential to work on multidisciplinary approaches and diverse strategies for developing new compounds acting on novel antibacterial targets. N-acetylglucosamine-1-phosphateuridyltransferase/ glucosamine-1-phosphate-acetyltransferase (GlmU) is one such target which is involved in the synthesis of both peptidoglycan and Lipopolysaccharide in Gram negative and Gram positive bacteria making GlmU an attractive target for developing antibacterials.

Results: GlmU, as revealed by X- ray crystallographic studies, is made up of two domains connected by α helical arm; the N-terminal uridyltransferase domain resembles a dinucleotide Rossmann fold and the C- terminal acetyltransferase domain adopts a left handed parallel β helix structure. The GlmU molecules are arranged in a trimeric array, the acetyltransferase active site being formed at the junction of adjacent LβH domain. Many potent inhibitors of both the acetyltransferase and uridyltransferase activity of GlmU have been identified. Inhibitors of the acetyltransferase activity of GlmU include nonspecific thiol reactive agents, 2-phenylbenzofurans, arylamines and arylsulfonamides. A aminopiperidine based inhibitor has also been reported to inhibit uridyltransferase activity of hiGlmU.

Conclusion: The present review provides an insight of the structure of GlmU and its reported inhibitors which make GlmU a potential target for drug designing. The GlmU is a promising target for drug discovery against Gram negative pathogens and future studies should focus on GlmU for the development of more potent compounds for treating Gram negative infections.

Keywords: GlmU, peptidoglycan, lipopolysaccharide, antibiotics, arylsulfonamide, inhibitors.

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Article Details

VOLUME: 18
ISSUE: 14
Year: 2017
Page: [1587 - 1597]
Pages: 11
DOI: 10.2174/1389450117666160502152011
Price: $58

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