Abstract
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 (IC50 = 10.2 μM), targeted the DNA-binding domain of PmrA (KD = 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.
MeSH terms
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / metabolism
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Benzenesulfonates / pharmacology*
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism
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Drug Discovery*
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Drug Resistance, Microbial / drug effects
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Klebsiella pneumoniae / drug effects
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Microbial Sensitivity Tests
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Oxazoles / pharmacology*
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Polymyxin B / pharmacology*
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Protein Binding
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Benzenesulfonates
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DNA-Binding Proteins
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Oxazoles
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pmrA protein, Bacteria
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DNA
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Polymyxin B