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.
Subject(s)
Antitubercular Agents/pharmacology , Autophagy/drug effects , Mycobacterium tuberculosis/drug effects , Phenanthrolines/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , 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/genetics , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/isolation & purification , Nitroimidazoles/pharmacology , Structure-Activity Relationship , THP-1 CellsABSTRACT
TMPRSS4 is a novel type II transmembrane serine protease that has been implicated in the invasion and metastasis of colon cancer cells. In this study, a novel series of 2-hydroxydiarylamide derivatives were synthesized and evaluated for inhibiting TMPRSS4 serine protease activity and suppressing cancer cell invasion. These derivatives demonstrated good inhibitory activity against TMPRSS4 serine protease, which correlated with the promising anti-invasive activity of colon cancer cells overexpressing TMPRSS4.
