Abstract
Industry screens of large chemical libraries have traditionally relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyperactivity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich, media, RBT was 200-fold more potent than rifampin. RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT, but not rifampin, through fhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acinetobacter Infections / drug therapy
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Acinetobacter Infections / microbiology
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Acinetobacter baumannii / drug effects*
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Acinetobacter baumannii / genetics
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Animals
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / drug effects
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Bacterial Proteins / genetics
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Colistin / pharmacology
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Disease Models, Animal
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Drug Resistance, Multiple, Bacterial / drug effects*
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Drug Resistance, Multiple, Bacterial / genetics
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Gene Deletion
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Gene Expression Regulation, Bacterial
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High-Throughput Screening Assays
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Male
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Mice
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Mice, Inbred C3H
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Microbial Sensitivity Tests
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Nutrients / metabolism*
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Receptors, Cell Surface / drug effects
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Receptors, Cell Surface / genetics
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Rifabutin / pharmacology*
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Rifampin / pharmacology
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Receptors, Cell Surface
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Rifabutin
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Rifampin
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Colistin