The quest for the holy grail: new antitubercular chemical entities, targets and strategies

Abstract

Tuberculosis (TB) remains the leading cause of death from an infectious disease worldwide. TB therapy is complicated by the protracted treatment regimens, development of resistance coupled with toxicity and insufficient sterilizing capacity of current drugs. Although considerable progress has been made on establishing a TB drug pipeline, the high attrition rate reinforces the need to continually replenish the pipeline with high-quality leads that act through inhibition of novel targets. In this review, we highlight some of the key advances that have assisted TB drug discovery with novel chemical matter, targets and strategies - to fuel the TB drug pipeline.

Figure 1

Novel antitubercular compounds. Chemical structures of the promising compounds in preclinical development (TB47, spectinamide 1810 and CPZEN-45) and novel chemical scaffolds (GSK656, AAP1, benzimidazole, 1,2,4-triazole, benzofuroxan, imidazol[2,1-b]thiazole-5-carboxamides and SMARt-420) with their MIC₉₀ values against Mycobacterium tuberculosis H37Rv strain, where applicable.

Figure 2

Attractive drug targets. Molecular targets that have been genetically and chemically validated in recent years, with significant progress in their biochemical characterization. The chemical validation is supported by many active inhibitors or at least one active compound. The presented molecular targets have not been targeted by any clinically used first-line anti-TB drugs, making them suitable for targeting MDR or XDR Mycobacterium tuberculosis strains. Impairment of their functions leads to the disrupted: (i) nucleic acid synthesis by targeting DNA gyrase – GyrA/B or DNA polymerase III sliding clamp – DnaN (shown by blue dashed line); (ii) cell wall biosynthesis by targeting mycobacterial membrane protein large 3 – MmpL3, decaprenylphosphoryl-β-d-ribose 2′-oxidase – DprE1, fatty acyl-AMP ligase – FadD32 or polyketide synthase – Pks13 (indicated by red dashed line); (iii) oxidative phosphorylation by targeting cytochrome bc₁ complex subunit B – QcrB (indicated by green dashed line); (iv) antibiotic efflux by targeting efflux pump – EfpA (indicated by orange dashed line); and (v) intermediate metabolism by targeting caseinolytic protease complex – Clp or phosphopantetheinyl transferase – PptT (indicated by black dashed line). Abbreviations: dsDNA, double-strand DNA; TMM, trehalose monomycolate; DPR, decaprenylphosphoryl-β-d-ribose; DPA, decaprenylphosphoryl-β-d-arabinose, CoA, coenzyme A; ACP, acyl carrier protein. The illustration was created using BioRender.

Figure 3

Novel strategies in anti-TB drug discovery. Highlighting some of the new strategies and techniques that can be used to combat tuberculosis (TB). Target-based whole-cell screening, CRISPR interference and PROSPECT utilize the recombinant Mycobacterium tuberculosis strains (OEs or cKDs), enabling identification or confirmation of the molecular target of the hit compound from whole-cell screening. Targeting nonreplicating and/or persistent M. tuberculosis, Caseum assays and host-directed therapy are focusing on host environment during the M. tuberculosis infection. Abbreviations: cKD, conditional knockdown; OE, overexpressor; CRISPR, clustered regularly interspersed short palindromic repeats; ATc, anhydrotetracycline; sgRNA, single guide RNA; dCas9, catalytically inactive (dead) nuclease Cas9; Mtb, M. tuberculosis; PROSPECT, primary screening of strains to prioritize expanded chemistry and targets; NRP, nonreplicating. The definition of foamy macrophage is described in Box 1. The illustration was created using BioRender.