Abstract
The global epidemic of tuberculosis (TB) imposes a sustained epidemiologic vigilance and investments in research by governments. Mycobacterium tuberculosis, the main causative agent of TB in human beings, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2018, ~10 million individuals were contaminated with this bacillus and became ill with TB, and about 1.2 million succumbed to the disease. Most of the success of the M. tuberculosis to linger in the population comes from its ability to persist in an asymptomatic latent state into the host and, in fact, the majority of the individuals are unaware of being contaminated. Even though TB is a treatable disease and is curable in most cases, the treatment is lengthy and laborious. In addition, the rise of resistance to first-line anti-TB drugs elicits a response from TB research groups to discover new chemical entities, preferably with novel mechanisms of action. The pathway to find a new TB drug, however, is arduous and has many barriers that are difficult to overcome. Fortunately, several approaches are available today to be pursued by scientists interested in anti-TB drug development, which goes from massively testing chemical compounds against mycobacteria, to discovering new molecular targets by genetic manipulation. This review presents some difficulties found along the TB drug development process and illustrates different approaches that might be used to try to identify new molecules or targets that are able to impair M. tuberculosis survival.
Highlights
Human tuberculosis (TB), mainly caused by the bacterial pathogen Mycobacterium tuberculosis, is a chronic, infectious-contagious, and deadly disease that has reached pandemic proportions
It is estimated that in 2018, an average of 6.2% of multidrug-resistant TB (MDR-TB) patients were infected with extensively drug-resistant strains of M. tuberculosis (XDR-TB) (World Health Organization, 2019), which is defined as MDR-TB plus resistance to at least one of the fluoroquinolones and one of the injectable second-line agents used in MDR-TB treatment regimens
The complete genome sequencing of M. tuberculosis H37Rv strain has accelerated the study and validation of molecular targets aiming at the rational design of anti-TB drugs (Cole et al, 1998)
Summary
Human tuberculosis (TB), mainly caused by the bacterial pathogen Mycobacterium tuberculosis, is a chronic, infectious-contagious, and deadly disease that has reached pandemic proportions. It is estimated that in 2018, an average of 6.2% of MDR-TB patients were infected with extensively drug-resistant strains of M. tuberculosis (XDR-TB) (World Health Organization, 2019), which is defined as MDR-TB plus resistance to at least one of the fluoroquinolones (such as ofloxacin, levofloxacin or moxifloxacin) and one of the injectable second-line agents used in MDR-TB treatment regimens (amikacin, capreomycin, or kanamycin). New chemical agents should be developed to allow affordable, simpler and faster TB treatment of pan-sensitive strains to increase patient adherence, be effective against drug-resistant strains, cut the risk of progression to active TB in latently infected individuals, and, ideally, result in sterilization of bacilli from infected patients (defined as clearance of the entire microbial population from all tissues of the host). Several peculiarities of the bacilli biology and the TB pathology, together with old challenges of the pharmacology field, are recognized to complicate the development of new effective therapies, and they should all be taken into consideration during the long journey of the TB drug development process
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