Journal
NATURE MICROBIOLOGY
Volume 5, Issue 9, Pages 1134-1143Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41564-020-0737-6
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Funding
- National Institute of Allergy and Infectious Diseases [R01AI139052, R01AI130060, R01AI117211]
- FDA (BAA contract) [HHSF223201710199C]
- Bill AMP
- Melinda Gates Foundation [OPP1107194]
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In this Article, using a nutrient-limited, media-based compound screening, the authors discover that the old antibiotic rifabutin is highly active against extensively drug-resistant Acinetobacter baumannii. 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.
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