ACS Infectious Diseases p. 3015 - 3025 (2020)
Update date:2022-08-28
Topics:
Székely, Rita
Rengifo-Gonzalez, Monica
Singh, Vinayak
Riabova, Olga
Benjak, Andrej
Piton, Jérémie
Cimino, Mena
Kornobis, Etienne
Mizrahi, Valerie
Johnsson, Kai
Manina, Giulia
Makarov, Vadim
Cole, Stewart T.
Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion and investigation of the structure activity relationship, selected modifications to the dioxo moiety of the DBPI scaffold were either neutral or led to reduction or abolition of antimycobacterial activity. To find the target, DBPI-resistant mutants of M. tuberculosis Erdman were raised and characterized first microbiologically and then by whole genome sequencing. Four different mutations, all affecting highly conserved residues, were uncovered in the essential gene rv0338c (ispQ) that encodes a membrane-bound protein, named IspQ, with 2Fe-2S and 4Fe-4S centers and putative iron-sulfur-binding reductase activity. With the help of a structural model, two of the mutations were localized close to the 2Fe-2S domain in IspQ and another in transmembrane segment 3. The mutant genes were recessive to the wild type in complementation experiments and further confirmation of the hit-target relationship was obtained using a conditional knockdown mutant of rv0338c in M. tuberculosis H37Rv. More mechanistic insight was obtained from transcriptome analysis, following exposure of M. tuberculosis to two different DBPI; this revealed strong upregulation of the redox-sensitive SigK regulon and genes induced by oxidative and thiol-stress. The findings of this investigation pharmacologically validate a novel target in tubercle bacilli and open a new vista for tuberculosis drug discovery.
View MoreQuhua Zhongxing Refrigeration Technology Co.,Ltd.
Contact:+86-5708886618
Address:318 Bulding 2, No.866 Quhua Rd.,Kecheng District
Jiangsu Chiatai Qingjiang Pharmaceutical Co.,Ltd
Contact:+86-517-86283327
Address:9 North Hantai Road, Huaian, China
qingdao goldenchem imp and exp co.,ltd.
Contact:532-55579246
Address:no.62 ,haier road laoshan distirct
Zhongshan Haihong Medicine Co., Ltd.
Contact:86-0760-86925778 (0)18824993998
Address:A7 building,lianyuan road Torch Hi-tech Industrial Development Zone
website:http://www.maisonchem.com.cn
Contact:0086-311-83833777
Address:Leitou industrial district, xinji, shijiazhuang city, hebei province,
Doi:10.1016/j.abb.2014.10.007
(2014)Doi:10.1002/jlcr.2590020204
(1966)Doi:10.1039/jr9500000371
(1950)Doi:10.1139/v69-019
(1969)Doi:10.1007/s11172-020-2799-2
(2020)Doi:10.1021/acs.jmedchem.0c01272
(2020)