A screen for and validation of prodrug antimicrobials

Laura E. Fleck, E. Jeffrey North, Richard E. Lee, Lawrence R. Mulcahy, Gabriele Casadei, Kim Lewis

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The rise of resistant pathogens and chronic infections tolerant to antibiotics presents an unmet need for novel antimicrobial compounds. Identifying broad-spectrum leads is challenging due to the effective penetration barrier of Gram-negative bacteria, formed by an outer membrane restricting amphipathic compounds, and multidrug resistance (MDR) pumps. In chronic infections, pathogens are shielded from the immune system by biofilms or host cells, and dormant persisters tolerant to antibiotics are responsible for recalcitrance to chemotherapy with conventional antibiotics. We reasoned that the dual need for broad-spectrum and sterilizing compounds could be met by developing prodrugs that are activated by bacterium-specific enzymes and that these generally reactive compounds could kill persisters and accumulate over time due to irreversible binding to targets. We report the development of a screen for prodrugs, based on identifying compounds that nonspecifically inhibit reduction of the viability dye alamarBlue, and then eliminate generally toxic compounds by testing for cytotoxicity. A large pilot of 55,000 compounds against Escherichia coli produced 20 hits, 3 of which were further examined. One compound, ADC111, is an analog of a known nitrofuran prodrug nitrofurantoin, and its activity depends on the presence of activating enzymes nitroreductases. ADC112 is an analog of another known antimicrobial tilbroquinol with unknown mechanism of action, and ADC113 does not belong to an approved class. All three compounds had a good spectrum and showed good to excellent activity against persister cells in biofilm and stationary cultures. These results suggest that screening for overlooked prodrugs may present a viable platform for antimicrobial discovery.

Original languageEnglish (US)
Pages (from-to)1410-1419
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume58
Issue number3
DOIs
StatePublished - Mar 1 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Fleck, L. E., North, E. J., Lee, R. E., Mulcahy, L. R., Casadei, G., & Lewis, K. (2014). A screen for and validation of prodrug antimicrobials. Antimicrobial agents and chemotherapy, 58(3), 1410-1419. https://doi.org/10.1128/AAC.02136-13