A nutrient-limited screen unmasks rifabutin hyperactivity for extensively drug-resistant Acinetobacter baumannii

Nat Microbiol. 2020 Sep;5(9):1134-1143. doi: 10.1038/s41564-020-0737-6. Epub 2020 Jun 8.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acinetobacter Infections / drug therapy
  • Acinetobacter Infections / microbiology
  • Acinetobacter baumannii / drug effects*
  • Acinetobacter baumannii / genetics
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / drug effects
  • Bacterial Proteins / genetics
  • Colistin / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Resistance, Multiple, Bacterial / genetics
  • Gene Deletion
  • Gene Expression Regulation, Bacterial
  • High-Throughput Screening Assays
  • Male
  • Mice
  • Mice, Inbred C3H
  • Microbial Sensitivity Tests
  • Nutrients / metabolism*
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / genetics
  • Rifabutin / pharmacology*
  • Rifampin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Receptors, Cell Surface
  • Rifabutin
  • Rifampin
  • Colistin