Abstract
Roughly a third of the world’s population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development.
Highlights
Mycobacterium tuberculosis is the main causative agent of human tuberculosis (TB)
The biosynthesis of aromatic rings from carbohydrate precursors in microorganisms and plants involves a range of extraordinary chemical transformations that together constitute the shikimate pathway; through seven enzymatic steps (Figure 1), phosphoenolpyruvate (PEP) and D-erythrose
Tuberculosis chorismate mutase (MtCM), which acts athetero-octameric the branch pointcomplex that connects thetuberculosis shikimate chorismate mutase (MtCM), which acts at the branch point that connects the shikimate pathway to pathway to produced by the (Phe) and Tyr production [26,37,38]
Summary
In 2018, approximately 10 million people developed TB, which resulted in 1.3 million deaths in HIV-negative and 300,000 deaths in HIV-positive patients This recent report from the World Health Organization (WHO) indicated that, worldwide, approximately 400,000 people developed multidrug-resistant TB (MDR-TB), where M. tuberculosis strains are resistant to isoniazid and rifampicin, two of the most effective TB first-line drugs [1]. Persisters are defined by a quiescent (non-growing or slow-growing) subpopulation of organisms that survive exposure to a bactericidal antibiotic, are genetically indistinct from drug-susceptible bacteria and can revive under antibiotic-free conditions [2] They are associated with reduced metabolic rate, activated stress response and altered cell-wall permeability when compared to drug-susceptible bacilli, and are primarily established in macrophages or granulomatous lesions inside the human host.
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