Novel lead generation of an anti-tuberculosis agent active against non-replicating mycobacteria: exploring hybridization of pyrazinamide with multiple fragments View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2015-07

AUTHORS

Shankar D. Markad, Parvinder Kaur, B. K. Kishore Reddy, Murugan Chinnapattu, Anandkumar Raichurkar, Radha Nandishaiah, Manoranjan Panda, Pravin S. Iyer

ABSTRACT

The key to shortening tuberculosis (TB) drug regimen lies in eliminating the reservoir of non-replicating persistent (NRP) Mycobacterium tuberculosis (Mtb). Pyrazinamide (PZA) is the only known drug used as part of a combination therapy that is believed to kill NRP Mtb and achieve sterilization. PZA is active only under low pH screening conditions. Screening and identification of NRP-active anti-TB compounds are severely limited because compounds are usually inactive under regular assay conditions. In an effort to design novel NRP-active anti-TB compounds, we used pyrazinamide as a core and hybridized it with the fragments derived from marketed drugs. One of these designs, compound 8, was a hybrid with fluoroquinolone. This compound exhibited >10 fold improvement in NRP activity under low pH condition as compared to pyrazinamide and a modest activity (0.8 log10 kill) under nutritionally starved NRP condition. Furthermore, compound 8 was active against fluoroquinolone-resistant strains and did not show any activity in a DNA supercoiling assay (gyrase inhibition), suggesting that its mechanism of action is not that of the parent fluoroquinolone. These results provide a novel avenue in the exploration of new chemotypes that are active against non-replicating Mtb. More... »

PAGES

2986-2992

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00044-015-1352-6

DOI

http://dx.doi.org/10.1007/s00044-015-1352-6

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https://app.dimensions.ai/details/publication/pub.1000480215


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