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.

Two Decades of TB Drug Discovery Efforts—What Have We Learned?

“…This is a biology-driven effort where compound libraries are screened for antimycobacterial activity against mycobacterial cells in culture, and the 'hits' are progressed based on the potency both in vitro and in vivo [69]. This cell-based approach has been successful from the early days of TB discovery, and most of the frontline drugs were progressed based on the structure-activity relationship that was evaluated directly on the whole cells.…”

“…However, these drugs were initially identified as inhibitors of the rapidly multiplying pathogen under in vitro culture conditions. It is generally accepted that the MTB population in the human host is a heterogeneous collection of the multiple 'physiological states' [69] that could indeed be a dynamic interchanging state. This raises two questions:…”

Morphological profiling of tubercle bacilli identifies drug pathways of action

“…Tuberculosis treatment is lengthy, lasting from 4 mo to over a year (1). The difficult regimen, rate of relapse, and incidence of drug resistant Mtb has motivated a significant effort to develop new antibacterial compounds that are effective in sterilizing Mtb infection (2). Many new drug classes and derivative compounds have been developed (2), but rapidly identifying the primary and secondary pathways of action is often a protracted process due to the difficulty in generating resistant mutants and dissecting the broad-reaching metabolic effects of drug treatment (3).…”

Morphological profiling of tubercule bacilli identifies drug pathways of action

“…Tuberculosis treatment is lengthy, lasting between four months to over a year (1). The difficult regimen, rate of relapse, and incidence of drug resistant Mtb has motivated a significant effort to develop new antibacterial compounds that are effective in sterilizing Mtb infection (2). Many new drug classes and derivative compounds have been developed (2), but rapidly identifying the primary and secondary pathways of action of each compound is often a protracted process due to the difficulty in generating resistant mutants, and dissecting the broad-reaching metabolic effects of drug treatment leading to death (3).…”

“…The difficult regimen, rate of relapse, and incidence of drug resistant Mtb has motivated a significant effort to develop new antibacterial compounds that are effective in sterilizing Mtb infection (2). Many new drug classes and derivative compounds have been developed (2), but rapidly identifying the primary and secondary pathways of action of each compound is often a protracted process due to the difficulty in generating resistant mutants, and dissecting the broad-reaching metabolic effects of drug treatment leading to death (3). Furthermore, drug action on bacterial cells can elicit dynamic responses in multiple pathways both on- and off-target, some of which are specific to bacterial growth environment and treatment dose (4–6).…”