Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2017 Oct 24;61(11):e00969-17. doi: 10.1128/AAC.00969-17. Print 2017 Nov.

Abstract

New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for in vitro activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens.

Keywords: 5-nitro-1,10-phenanthroline; F420 dependence; Mycobacterium tuberculosis; autophagy; phenotypic screening.

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Escherichia coli / drug effects
  • Female
  • Humans
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mycobacterium bovis / drug effects
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / isolation & purification
  • Nitroimidazoles / pharmacology
  • Phenanthrolines / pharmacology*
  • Structure-Activity Relationship
  • THP-1 Cells
  • Tuberculosis, Multidrug-Resistant / drug therapy*

Substances

  • 5-nitro-1,10-phenanthroline
  • Antitubercular Agents
  • Nitroimidazoles
  • Phenanthrolines
  • pretomanid