The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

Abstract

This article provides an encompassing review of the current pipeline of putative and developed treatments for tuberculosis, including multidrug-resistant strains. The review has organized each compound according to its site of activity. To provide context, mention of drugs within current recommended treatment regimens is made, thereafter followed by discussion on recently developed and upcoming molecules at established and novel targets. The review is designed to provide a clinically applicable understanding of the compounds that are deemed most currently relevant, including those already under clinical study and those that have shown promising pre-clinical results. An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided. The three levels of the bacterial cell wall (mycolic acid, arabinogalactan, and peptidoglycan layers) are highlighted and important compounds designed to target each layer are delineated. Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating this ancient scourge.

Fig. 1

The mycobacterial cell wall with target sites of current therapies and those in development. Reproduced with permission from Elsevier Masson from: Shanib Bhat Z, Ahmad Rather M, Maqbool M, Lah HU, Khalid Yousuf S, Ahmad Z. Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis. Biomed Pharmacother. 2017;95:1520–34 [8]

Fig. 2

2022 global new tuberculosis (TB) drug pipeline, updated 3 November 2022. Reproduced with permission from the: Stop TB Partnership Working Group on New TB Drugs [7]. Figure is available at: www.newtbdrugs.org/pipeline/clinical