Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

Abstract

Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host's immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB-the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years-reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.

Keywords: TB pathogenesis; TB treatment regimens; anti-TB drug candidates; latent TB; mycobacterial drug targets; tuberculosis.

Figure 1

General TB statistics and main symptoms of pulmonary TB.

Figure 2

Pathophysiology of pulmonary TB. Following the M. tb transmission to the new host, the bacilli enter the lung and get ingested by macrophages. Further immune cells are recruited to wall off the infected macrophages, leading to the formation of the granuloma, the hallmark of TB. Healthy individuals remain latently infected, and the infection is kept at bay at this stage, but it is prone to the risk of reactivation. Foamy macrophages release their lipid content when they necrotise, leading to caseation (cheese-like structure). Caseum is a decay manifested at the core of the granuloma that compromise its rigid integrity. As the granuloma develops, the bacilli commence to seep out of the macrophages into the caseum layer. When the reactivation occurs, M. tb proliferates and the bacterial load becomes overwhelmingly high, whereupon the granuloma rupture, disseminating the bacteria to the airways. The bacilli are then expectorated as contagious aerosol droplets, restarting the cycle, infecting other individuals.

Figure 3

The four front-line anti-TB drugs.

Figure 4

Current second-line anti-TB agents.

Figure 5

A simplified diagram of target-based and phenotypic TB drug discovery cascade.

Figure 6

Schematic representation of the site of action of several current promising anti-TB drug candidates and hit/lead compounds. A simple version of the mycobacterial cell wall and the cytoplasmic membrane is portrayed, showing the current hot targets in TB drug discovery, namely GyrA/B, QcrB, ATP synthase, DprE1, FadD32, Pks13 and MmpL3. TMM: trehalose monomycolate, GroMM: glycerol monomycolate, TDM: trehalose dimycolate, GMM: glucose monomycolate (GMM), DPR: decaprenylphosphoryl-D-ribose, DPX: decaprenylphosphoryl-2′-ketoribose, DPA: decaprenylphosphoryl-D-arabinose, MAs: mycolic acids, FAS-I: fatty acid synthase I and FAS-II: fatty acid synthase II.