Implications of Chromosomal Mutations for Mycobacterial Drug Resistance

Tuberculosis (TB) remains a global health concern, despite availability of antituberculosis drugs. Drug-resistant Mycobacterium tuberculosis strains were identified shortly after the discovery and introduction of streptomycin for the treatment of this disease. Subsequently, multidrug therapy was implemented for TB treatment; however, this was soon followed by reports of multi-, extensively, and totally drug-resistant tuberculosis cases globally. The amplification of this drug resistance is due to the sequential accumulation of chromosomal alterations in target genes in the Mycobacterium tuberculosis genome. It is also evident that the presence of mutations that confer drug resistance results in the emergence of compensatory mechanisms which restore bacterial fitness. The recent approval by the Food and Drug Administration for bedaquiline as an antituberculosis drug provided some hope. However, clinical resistance to this new drug has already been reported. This underscores that it is imperative to understand drug resistance and its associated mechanisms in order to direct research efforts to the development of antituberculosis regimens with novel mechanisms of actions.