Protein-DNA complex-guided discovery of the antibacterial lead for restoring the susceptibility of to polymyxin B by targeting the response regulator PmrA

A new antibacterial drug is urgently needed. We employed a protein-DNA complex-guided pharmacophore modeling approach to screen inhibitors against the response regulator PmrA of polymyxin B-resistant Klebsiella pneumoniae (KP). The identified lead, E1 (IC 50 = 10.2 μM), targeted the DNA-binding doma...

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Published inChemical communications (Cambridge, England) Vol. 54; no. 49; pp. 6372 - 6375
Main Authors Tseng, Tien-Sheng, Tu, I-Fan, Chen, Hsiao-Ting, Lin, Lie-Chwen, Tsai, Keng-Chang, Wu, Shih-Hsiung, Chen, Chinpan
Format Journal Article
Published 14.06.2018
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Summary:A new antibacterial drug is urgently needed. We employed a protein-DNA complex-guided pharmacophore modeling approach to screen inhibitors against the response regulator PmrA of polymyxin B-resistant Klebsiella pneumoniae (KP). The identified lead, E1 (IC 50 = 10.2 μM), targeted the DNA-binding domain of PmrA ( K D = 1.7 μM), whose conserved residues R171, R198, K203, and Y214 have been shown to be hotspots for antimicrobial development. Treatment of E1 restored the susceptibility of KP to polymyxin B. E1 , a novel adjuvant lead, restored the susceptibility of Klebsiella Pneumoniae to Polymyxin B by targeting the response regulator PmrA.
Bibliography:10.1039/c8cc01840e
Electronic supplementary information (ESI) available. See DOI
ISSN:1359-7345
1364-548X
DOI:10.1039/c8cc01840e