Optimizing the use of current antituberculosis drugs to overcome drug resistance in Mycobacterium tuberculosis

Abstract

Antibiotic-resistant tuberculosis continues to be one of the major threats to global tuberculosis control. After a hiatus of over 40 years in antituberculosis drug development, the last decade has seen a resurgence of research, yielding a number of promising compounds in the tuberculosis drug pipeline, with some that are now game changers in the treatment of MDRTB. Despite this progress, there are still obstacles restricting the use of these molecules as first-line drugs. The quick appearance of bacteria resistant to these new treatments highlights a continuing need to fuel the discovery and development of new molecules. With this in mind, alternative strategies aimed at optimizing the utilization of existing antituberculosis agents are currently under evaluation. They are focused on enhancing the efficacy of antibiotics against their bacterial targets, primarily by augmenting the quantity of antibiotic that engages with these targets. This objective can be achieved through two primary approaches: (1) Provided that toxicity concerns are not a limiting factor, increased dosing is a viable avenue, as demonstrated by rifampicin, isoniazid, and fluoroquinolones, for which escalated dosing has been effective; and (2) Employing enhancers such as drug activator boosters (ethionamide), efflux pump inhibitors, or hydrolytic enzyme inhibitors (kanamycin) can elevate the concentration of antibiotics in bacterial cells. These strategies offer the potential to mitigate antibiotic obsolescence and complement the discovery of new antibiotics.