Strategies in anti-Mycobacterium tuberculosis drug discovery based on phenotypic screening

Abstract

The rise of multi- and extensively drug-resistant Mycobacterium tuberculosis (M. tb) strains and co-infection with human immunodeficiency virus has escalated the need for new anti-M. tb drugs. Numerous challenges associated with the M. tb, in particular slow growth and pathogenicity level 3, discouraged use of this organism in past primary screening efforts. From current knowledge of the physiology and drug susceptibility of mycobacteria in general and M. tb specifically, it can be assumed that many potentially useful drug leads were missed by failing to screen directly against this pathogen. This review discusses recent high-throughput phenotypic screening strategies for anti-M. tb drug discovery. Emphasis is placed on prioritization of hits, including their extensive biological and chemical profiling, as well as the development status of promising drug candidates discovered with phenotypic screening.

Fig. 1

The chemical structures of anti-M. tb compounds in clinical trials: a bedaquiline, b delamanid, c pretomanid, d SQ109, and e Q203

Fig. 2

The scheme of preparation of the actinomycetes library

Fig. 3

The prioritization workflow of the high-throughput screening campaigns of the actinomycetes libraries

Fig. 4

The chemical structures of a ecumicin, b rufomycin, c cyclomarin A, and d lassomycin