Revisiting tuberculosis therapy
Despite its decreasing incidence, TB remains one of the biggest health issues in the developing world, affecting millions of people. Antitubercular therapy is compromised by the emergence of multidrug-resistant Mycobacterium tuberculosis strains. These are treated with second-line drugs that are however less effective, more toxic and expensive. Lack of treatment adherence in endemic countries has exacerbated the problem by inducing extremely drug-resistant TB. As a result, it is of paramount importance to identify and develop novel drugs that are effective against both drug-susceptible and drug-resistant TB. With this in mind, researchers on the EU-funded ORCHID (Open collaborative model for tuberculosis lead optimisation) project set out to discover compounds that could serve as antituberculosis drugs. The consortium was particularly interested in three compound families – namely, beta-lactam antibiotics, novel compounds and inhibitors of the InhA enzyme, which is implicated in mycobacterium metabolism. Through chemical synthesis and genetic/proteomic studies, researchers discovered whole cell inhibitors that were subsequently screened for their antimycobacterial activity in in vitro assays. The team screened and prioritised 250 000 compounds based on their antitubercular potency and physicochemical properties. Regarding the beta-lactam antibiotics, the candidate faropenem showed promising properties and progressed to clinical testing as an antituberculosis oral agent. This data challenged the reported inefficiency of beta-lactams as antitubercular drugs and demonstrated that known antibiotics could be shifted towards the treatment of tuberculosis. Promising results were also obtained with thiadiazole InhA enzyme inhibitors in combination with various antitubercular drugs. They also addressed the delivery of these drugs through different innovative formulations based on mesoporous silica. A further major achievement of the study was discovery of a new family of compounds that selectively killed latent stages of Mycobacterium tuberculosis. These drugs induced bacterial cell death through the accumulation of toxic intermediates. Overall, ORCHID was successful in its antitubercular screening efforts. The novel compounds identified during the study could serve as alternative treatment regimens for drug-resistant TB.
Keywords
Tuberculosis, lead compounds, drug-resistant, mycobacterium, beta-lactam, InhA enzyme