Advances in Diagnostics and Drug Discovery against Resistant and Latent Tuberculosis Infection

Abstract

Latent tuberculosis infection (LTBI) represents a subclinical, asymptomatic mycobacterial state affecting approximately 25% of the global population. The substantial prevalence of LTBI, combined with the risk of progressing to active tuberculosis, underscores its central role in the increasing incidence of tuberculosis (TB). Accurate identification and timely treatment are vital to contain and reduce the spread of the disease, forming a critical component of the global strategy known as "End TB." This review aims to examine and highlight the most recent scientific evidence related to new diagnostic approaches and emerging therapeutic treatments for LTBI. While prevalent diagnostic methods include the tuberculin skin test (TST) and interferon gamma release assay (IGRA), WHO's approval of two specific IGRAs for Mycobacterium tuberculosis (MTB) marked a significant advancement. However, the need for a specific test with global application viability has propelled research into diagnostic tests based on molecular diagnostics, pulmonary immunity, epigenetics, metabolomics, and a current focus on next-generation MTB antigen-based skin test (TBST). It is within these emerging methods that the potential for accurate distinction between LTBI and active TB has been demonstrated. Therapeutically, in addition to traditional first-line therapies, anti-LTBI drugs, anti-resistant TB drugs, and innovative candidates in preclinical and clinical stages are being explored. Although the advancements are promising, it is crucial to recognize that further research and clinical evidence are needed to solidify the effectiveness and safety of these new approaches, in addition to ensuring access to new drugs and diagnostic methods across all health centers. The fight against TB is evolving with the development of more precise diagnostic tools that differentiate the various stages of the infection and with more effective and targeted treatments. Once consolidated, current advancements have the potential to transform the prevention and treatment landscape of TB, reinforcing the global mission to eradicate this disease.

Keywords: Drug discovery; Latent tuberculosis infection; Mycobacterium tuberculosis; diagnostic.

Figure 1

TB progression: Macrophages attempt to eradicate MTB, which persists intracellularly and induces an inflammatory response, leading to granuloma formation. The infection may become latent or progressive, resulting in cavity rupture and bacterial dissemination. Created with Biorender.

Figure 2

Countries with LTBI incidence are classified according to their prevalence into high (red), intermediate (yellow), and low (light blue) categories, corresponding to prevalence ranges of 28–36%, 19–20%, and 3–5%, respectively.

Figure 3

Drug candidates with potential activity against LTBI in preclinical and clinical stages, their mechanisms of action, and chemical classes.

Figure 4

Scheme of the design of drugs based on benzofuroxan derivatives, and an example of the expansion of the chain of rings linked to the benzofuroxan nucleus. Reprinted from Fernandes et al. [129], with permission from the John Wiley and Sons License 2023.

Figure 5

Synthetic route for the preparation of final carbamate compounds 47–56. Reagents and conditions: (i) triphosgene, triethylamine, THF, 20 °C, 16 h. Reprinted from Fernandes et al. [130], with permission from the John Wiley and Sons License 2023.

Figure 6

(A) Synthesis of 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4). (B) Synthesis of sulfamethaoxazole 4-thiazolidinone hybrids (7a–l). (C) New Sulfamethaoxazole-based 4-thiazolidinone derivatives (1–5). Reprinted from Bhat et al. [131] with permission from the MDPI open access license 2020 and Scarim et al. [132] with permission from John Wiley and Sons License 2023.