Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline Against Mycobacterium Tuberculosis

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2017 Sep 13

PMID 28893784

Citations 18

Authors

Saqib Kidwai

Chan-Yong Park

Shradha Mawatwal

Prabhakar Tiwari

Myung Geun Jung

Tannu Priya Gosain

Pradeep Kumar

David Alland

Sandeep Kumar

Avinash Bajaj

Yun-Kyung Hwang

Chang Sik Song

Rohan Dhiman

Ill Young Lee

Ramandeep Singh

Affiliations

Soon will be listed here.

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 and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F-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 activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved activity and efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against , 5NP also modulates the host machinery to kill intracellular pathogens.

Citing Articles

Identification and optimization of pyridine carboxamide-based scaffold as a drug lead for .

Singh P, Kumar A, Sharma P, Chugh S, Kumar A, Sharma N Antimicrob Agents Chemother. 2024; 68(2):e0076623.

PMID: 38193667 PMC: 10848774. DOI: 10.1128/aac.00766-23.

Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line.

Rossini N, Dias M Genet Mol Biol. 2023; 46(1 Suppl 2):e20220261.

PMID: 36718771 PMC: 9887390. DOI: 10.1590/1678-4685-GMB-2022-0261.

Pharmacokinetic comparability between two populations using nonlinear mixed effect models: a Monte Carlo study.

Sahasrabudhe S, Bonate P J Pharmacokinet Pharmacodyn. 2023; 50(3):189-201.

PMID: 36708443 DOI: 10.1007/s10928-023-09842-2.

Structural and Functional Characterization of Rv0792c from Mycobacterium tuberculosis: Identifying Small Molecule Inhibitor against HutC Protein.

Chauhan N, Anand A, Sharma A, Dhiman K, Gosain T, Singh P Microbiol Spectr. 2022; 11(1):e0197322.

PMID: 36507689 PMC: 9927256. DOI: 10.1128/spectrum.01973-22.

NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs and .

Singh P, Rawat S, Agrahari A, Singh M, Chugh S, Gurcha S Microbiol Spectr. 2022; 10(6):e0259222.

PMID: 36314972 PMC: 9769743. DOI: 10.1128/spectrum.02592-22.

References

Tahlan K, Wilson R, Kastrinsky D, Arora K, Nair V, Fischer E . SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012; 56(4):1797-809. PMC: 3318387. DOI: 10.1128/AAC.05708-11. View

Bleicher K, Winter J . Purification and properties of F420- and NADP(+)-dependent alcohol dehydrogenases of Methanogenium liminatans and Methanobacterium palustre, specific for secondary alcohols. Eur J Biochem. 1991; 200(1):43-51. DOI: 10.1111/j.1432-1033.1991.tb21046.x. View

Zhu X, Li T, Gu X, Zhang S, Liu Y, Wang Y . Structural and functional investigation into acetyl-coenzyme A synthase and methyltransferase from human pathogen Clostridium difficile. Metallomics. 2013; 5(5):551-8. DOI: 10.1039/c3mt20257g. View

Singh R, Manjunatha U, Boshoff H, Ha Y, Niyomrattanakit P, Ledwidge R . PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 322(5906):1392-5. PMC: 2723733. DOI: 10.1126/science.1164571. View

Songane M, Kleinnijenhuis J, Netea M, van Crevel R . The role of autophagy in host defence against Mycobacterium tuberculosis infection. Tuberculosis (Edinb). 2012; 92(5):388-96. DOI: 10.1016/j.tube.2012.05.004. View

Shoji-Kawata S, Sumpter R, Leveno M, Campbell G, Zou Z, Kinch L . Identification of a candidate therapeutic autophagy-inducing peptide. Nature. 2013; 494(7436):201-6. PMC: 3788641. DOI: 10.1038/nature11866. View

Zumla A, Nahid P, Cole S . Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov. 2013; 12(5):388-404. DOI: 10.1038/nrd4001. View

Dawson R, Narunsky K, Carman D, Gupte N, Whitelaw A, Efron A . Two-stage activity-safety study of daily rifapentine during intensive phase treatment of pulmonary tuberculosis. Int J Tuberc Lung Dis. 2015; 19(7):780-6. PMC: 6783281. DOI: 10.5588/ijtld.14.0868. View

Zumla A, Raviglione M, Hafner R, von Reyn C . Tuberculosis. N Engl J Med. 2013; 368(8):745-55. DOI: 10.1056/NEJMra1200894. View

10.

Khorasani-Motlagh M, Noroozifar M, Moodi A, Niroomand S . Biochemical investigation of yttrium(III) complex containing 1,10-phenanthroline: DNA binding and antibacterial activity. J Photochem Photobiol B. 2013; 120:148-55. DOI: 10.1016/j.jphotobiol.2012.12.010. View

11.

Levine B, Deretic V . Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007; 7(10):767-77. PMC: 7097190. DOI: 10.1038/nri2161. View

12.

Gutierrez M, Master S, Singh S, Taylor G, Colombo M, Deretic V . Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004; 119(6):753-66. DOI: 10.1016/j.cell.2004.11.038. View

13.

Viganor L, Galdino A, Nunes A, Santos K, Branquinha M, Devereux M . Anti-Pseudomonas aeruginosa activity of 1,10-phenanthroline-based drugs against both planktonic- and biofilm-growing cells. J Antimicrob Chemother. 2015; 71(1):128-34. DOI: 10.1093/jac/dkv292. View

14.

Gopal M, Padayatchi N, Metcalfe J, ODonnell M . Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2013; 17(8):1001-7. PMC: 4003893. DOI: 10.5588/ijtld.12.0144. View

15.

Zumla A, Maeurer M . Host-directed therapies for multidrug resistant tuberculosis. Int J Mycobacteriol. 2017; 5 Suppl 1:S21-S22. DOI: 10.1016/j.ijmyco.2016.09.044. View

16.

Pym A, Diacon A, Tang S, Conradie F, Danilovits M, Chuchottaworn C . Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2015; 47(2):564-74. DOI: 10.1183/13993003.00724-2015. View

17.

Songane M, Kleinnijenhuis J, Alisjahbana B, Sahiratmadja E, Parwati I, Oosting M . Polymorphisms in autophagy genes and susceptibility to tuberculosis. PLoS One. 2012; 7(8):e41618. PMC: 3412843. DOI: 10.1371/journal.pone.0041618. View

18.

Diacon A, Lounis N, Dannemann B . Multidrug-resistant tuberculosis and bedaquiline. N Engl J Med. 2014; 371(25):2436. DOI: 10.1056/NEJMc1412235. View

19.

Tay C, Quah S, Lui J, Yu V, Tan K . Matrix Metalloproteinase Inhibitor as an Antimicrobial Agent to Eradicate Enterococcus faecalis Biofilm. J Endod. 2015; 41(6):858-63. DOI: 10.1016/j.joen.2015.01.032. View

20.

Sterling T, Scott N, Miro J, Calvet G, La Rosa A, Infante R . Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS. 2016; 30(10):1607-15. PMC: 4899978. DOI: 10.1097/QAD.0000000000001098. View