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Perspective: Challenges and Opportunities with phenotypic screens in TB drug discovery

Manjunatha, Ujjini Havaldar and Smith, Paul William (2015) Perspective: Challenges and Opportunities with phenotypic screens in TB drug discovery. Bioorganic & Medicinal Chemistry Special Issue.


Tuberculosis continues to pose a major global health problem and multi-drug resistant strains are becoming increasingly widespread worldwide, hence there continues to be an urgent need to discover new TB drugs. Cell based phenotypic screening represents a powerful approach to identify new anti-mycobacterial compounds and also to elucidate novel targets or pathways. Three high throughput phenotypic screens were carried out with the Novartis compound collection against mycobacterium over 5 years. This culminated in the identification of multiple hits from which several promising chemical series were selected for lead optimisation. This work generated a number of lead compounds with good in vitro anti-mycobacterial activity and good PK properties. Some of these molecules demonstrated oral activity against M. tuberculosis in mouse efficacy models. Herein, we provide an overview of the efforts at NITD and experiences in lead optimisation starting from phenotypic screening hits, describing some of the key challenges encountered and highlighting important lessons that we learnt which may be helpful for others working in this challenging field. We also offer some further perspectives based on our experience to facilitate future identification and advancement of tractable phenotypic hits.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12