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| 1 | Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars显示文摘New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting intracellularly.Mycobacteria have a unique cell wall.Deletion of the gene for arylamine N-acetyltransferase(NAT)decreases mycobacterial cell wall lipids,particularly the distinctive mycolates,and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis BCG.The nat gene and its associated gene cluster are almost identical in sequence in M.bovis BCG and M.tuberculosis.The gene cluster is essential for intracellular survival of mycobacteria.We have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT activity.Here,we characterize one class of such molecules—triazoles—in relation to its effects on the target enzyme and on both M.bovis BCG and M.tuberculosis.The most potent triazole mimics the effects of deletion of the nat gene on growth,lipid disruption and intracellular survival.We also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth,and use ligand-protein analysis to give further insight into the structure-activity relationships.We conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved. | Isaac M.Westwood Sanjib Bhakta Angela J.Russell Elizabeth Fullam Matthew C.Anderton Akane Kawamura Andrew W.Mulvaney Richard J.Vickers Veemal Bhowruth Gurdyal S.Besra Ajit Lalvani Stephen G.Davies Edith Sim | 2010 | Protein & Cell2010，1，1： | 3 |
| 2 | The evaluation of forty-three plant species for in vitro antimycobacterial activities; isolation of active constituents from Psoralea corylifolia and Sanguinaria canadensis显示文摘 | SANDRA M N CLARA L SUDAGAR S G GURDYAL S B COLIN W W | 2002 | Journal of Ethnopharmacology2002，79，1： | 1 |
| 3 | Lipid hydrolizing enzymes in virulence: Mycobacterium tuberculosis as a model system显示文摘 | Gurdyal Singh Gurpreet Singh Dipendrasinh Jadeja Jagdeep Kaur | 2010 | Critical Reviews in Microbiology2010，，3： | 1 |
| 4 | Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2显示文摘Inhibition of Mycobacterium tuberculosis(Mtb)cell wall assembly is an established strategy for anti-TB chemotherapy.Arabinosyltransferase EmbB,which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose(DPA)to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis.Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug,ethambutol.Herein,we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its'resting state'and DPA-bound'active state'.EmbB is a fifteen-transmembrane-spanning protein,assembled as a dimer.Each protomer has an associated acyl-carrier-protein(AcpM)on their cytoplasmic surface.Confor-mational changes upon DPA binding indicate an asym-metric movement within the EmbB dimer during catalysis.Functional studies have identified critical residues in substrate recognition and catalysis,and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA.The structures represent the first step directed towards a rational approach for anti-TB drug discovery. | Lu Zhang Yao Zha Ruogu Gao Jun Li Xiuna Yang Yan Gao Wei Zhao Sudagar S.Gurcha Natacha Veerapen Sarah M.Batt Kajelle Kaur Besra Wenqing Xu Lijun Bi Xian'en Zhang Luke W.Guddat Haitao Yang Quan Wang Gurdyal S.Besra Zihe Rao | 2020 | Protein & Cell2020，11，7： | 0 |
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