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Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis
Kidwai, Saqib,Park, Chan-Yong,Mawatwal, Shradha,Tiwari, Prabhakar,Jung, Myung Geun,Gosain, Tannu Priya,Kumar, Pradeep,Alland, David,Kumar, Sandeep,Bajaj, Avinash,Hwang, Yun-Kyung,Song, Chang Sik,Dhima American Society for Microbiology 2017 Antimicrobial Agents and Chemotherapy Vol.61 No.11
<B>ABSTRACT</B><P>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 <I>fbiB</I> 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 <I>in vitro</I> activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved <I>in vitro</I> activity and <I>in vivo</I> 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.</P>
Chakravorty, Soumitesh,Lee, Jong Seok,Cho, Eun Jin,Roh, Sandy S.,Smith, Laura E.,Lee, Jiim,Kim, Cheon Tae,Via, Laura E.,Cho, Sang-Nae,Barry III, Clifton E.,Alland, David American Society for Microbiology 2015 Journal of clinical microbiology Vol.53 No.1
<P>Resistance to amikacin (AMK) and kanamycin (KAN) in clinical <I>Mycobacterium tuberculosis</I> strains is largely determined by specific mutations in the <I>rrs</I> gene and <I>eis</I> gene promoter. We developed a rapid, multiplexed sloppy molecular beacon (SMB) assay to identify these mutations and then evaluated assay performance on 603 clinical <I>M. tuberculosis</I> DNA samples collected in South Korea. Assay performance was compared to gold-standard phenotypic drug susceptibility tests, including Lowenstein-Jensen (LJ) absolute concentration, mycobacterial growth indicator tubes (MGIT), and TREK Sensititre MycoTB MIC plate (MycoTB) methods. Target amplicons were also tested for mutations by Sanger sequencing. The SMB assay correctly detected 115/116 mutant and mixed sequences and 487/487 wild-type sequences (sensitivity and specificity of 99.1 and 100%, respectively). Using the LJ method as the reference, sensitivity and specificity for AMK resistance were 92.2% and 100%, respectively, and sensitivity and specificity for KAN resistance were 87.7% and 95.6%, respectively. Mutations in the <I>rrs</I> gene were unequivocally associated with high-level cross-resistance to AMK and KAN in all three conventional drug susceptibility testing methods. However, <I>eis</I> promoter mutations were associated with KAN resistance using the MGIT or MycoTB methods but not the LJ method. No testing method associated <I>eis</I> promoter mutations with AMK resistance. Among the discordant samples with AMK and/or KAN resistance but wild-type sequence at the target genes, we discovered four new mutations in the <I>whiB7</I> 5′ untranslated region (UTR) in 6/22 samples. All six samples were resistant only to KAN, suggesting the possible role of these <I>whiB7</I> 5′ UTR mutations in KAN resistance.</P>