Abstract
The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC90 values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 μg/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class.
Keywords:
Antibacterial agent; Antimicrobial resistance; Bacterial type II topoisomerase; DNA gyrase; Topoisomerase IV.
Copyright © 2020 Elsevier Ltd. All rights reserved.
MeSH terms
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Cell Survival / drug effects
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DNA Topoisomerases, Type II / metabolism*
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Dose-Response Relationship, Drug
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Drug Resistance, Bacterial / drug effects
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Hep G2 Cells
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Humans
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Methicillin-Resistant Staphylococcus aureus / enzymology
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Structure
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Streptococcus pneumoniae / drug effects
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Streptococcus pneumoniae / enzymology
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemical synthesis
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Topoisomerase II Inhibitors / chemistry
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Topoisomerase II Inhibitors / pharmacology*
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Transcriptional Regulator ERG / antagonists & inhibitors
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Transcriptional Regulator ERG / metabolism
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Vancomycin-Resistant Enterococci / drug effects
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Vancomycin-Resistant Enterococci / enzymology
Substances
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Anti-Bacterial Agents
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ERG protein, human
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Quinolines
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Topoisomerase II Inhibitors
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Transcriptional Regulator ERG
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DNA Topoisomerases, Type II