Tackling Drug-Resistant Tuberculosis: New Challenges from the Old Pathogen Mycobacterium tuberculosis

Abstract

Antibiotics have played a crucial role in the reduction in the incidence of TB globally as evidenced by the fact that before the mid-20th century, the mortality rate within five years of the onset of the disease was 50%. The use of antibiotics has eliminated TB as a devastating disease, but the challenge of resistance to anti-TB drugs, which had already been described at the time of the introduction of streptomycin, has become a major global issue in disease management. Mismanagement of multidrug-resistant tuberculosis (MDR-TB) cases, resulting from intermittent drug use, prescription errors, and non-compliance of patients, has been identified as a critical risk factor for the development of extensively drug-resistant tuberculosis (XDR-TB). Antimicrobial resistance (AMR) in TB is a multi-factorial, complex problem of microbes evolving to escape antibiotics, the gradual decline in antibiotic development, and different economic and social conditions. In this review, we summarize recent advances in our understanding of how Mycobacterium tuberculosis evolves drug resistance. We also highlight the importance of developing shorter regimens that rapidly reach bacteria in diverse host environments, eradicating all mycobacterial populations and preventing the evolution of drug resistance. Lastly, we also emphasize that the current burden of this ancient disease is driven by a combination of complex interactions between mycobacterial and host factors, and that only a holistic approach that effectively addresses all the critical issues associated with drug resistance will limit the further spread of drug-resistant strains throughout the community.

Keywords: M.tb pathogenesis; MDR-TB; XDR-TB; drug tolerance; new approaches.

Figure 1

Key milestones in the history of tuberculosis.

Figure 2

Schematic representation of tuberculosis pathogenesis. Infection with Mycobacterium tuberculosis occurs when aerosol droplets containing tubercle bacilli from an actively infected person reach the alveoli of an uninfected contact. In immunocompetent individuals, the host immune system fights infection by continuously recruiting and accumulating different morphotypes of macrophages, dendritic cells, B and T cells to form solid granulomas. This structure contains the bacilli, making healthy individuals latently infected (latent tuberculosis). As the disease advances, the granulomas undergo necrotic lysis of the immune cells, resulting in changes, and the center of the granuloma becomes caseous, which can lead to cavities in the lungs in the later stages of TB. If, for some reason, the host’s immune system fails to control the infection (such as in HIV or diabetes), the tubercle bacilli become active again, multiply, break out of the granuloma, and spread to other people, initiating the symptomatic phase of the disease (active TB).

Figure 3

Mechanisms of action and resistance of antibiotics in M. tuberculosis.