Abstract
Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Actinomycetales / chemistry
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Aminoglycosides / isolation & purification*
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Aminoglycosides / pharmacology*
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / isolation & purification
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Anti-Bacterial Agents / pharmacology
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DNA Gyrase / metabolism
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DNA Topoisomerase IV / antagonists & inhibitors
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DNA Topoisomerase IV / metabolism
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / isolation & purification
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Enzyme Inhibitors / pharmacology
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Escherichia coli / drug effects
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Escherichia coli / enzymology
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Magnetic Resonance Spectroscopy
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Microbial Sensitivity Tests
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Molecular Conformation
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Naphthalenes / isolation & purification*
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Naphthalenes / pharmacology*
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / enzymology
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Structure-Activity Relationship
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Topoisomerase II Inhibitors
Substances
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Aminoglycosides
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Naphthalenes
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Topoisomerase II Inhibitors
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kibdelomycin A
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DNA Topoisomerase IV
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DNA Gyrase