The emergence of extensively drug-resistant tuberculosis: a global health crisis requiring new interventions: Part II: scientific advances that may provide solutions

Abstract

The need for new tuberculosis (TB) diagnostics has never been greater as TB in the HIV-infected is often sputum smear negative or extrapulmonary and may progress rapidly unless diagnosed and treated appropriately. In addition, the empirical treatment of patients with drug-resistant TB leads to the acquisition of additional resistance. Fortunately there is a robust and adequately funded developments pipeline including investigational rapid diagnostics that may replace smear, culture, and drug susceptibility testing. The dogma that drug resistance usually develops as a consequence of patient nonadherence has never been entirely plausible. Recent observations indicate that certain mutations in drug resistance genes promote the acquisition of additional resistance. Further, Mycobacterium tuberculosis (MTB) may demonstrate tolerant phenotypes due to induction of a multidrug-resistant like pump. It will be difficult to "treat our way" out of the problem of extensively drug-resistant (XDR)-TB without access to new interventions. Vaccines in development offer a distant hope. Promising new therapeutics in clinical trials may shorten the duration of treatment of TB, which will lessen the development of drug resistance or provide potent new and MTB specific agents that should be effective in treatment of XDR-TB.

Figure 1

Visual detection of LAMP product under UV light. From left to right, tubes 1,2, 7, and 8 are positive; 3, 4, 5, and 6 are negative. Reprinted from Ref. 6 with permission.

Figure 2

Three‐dimensional (3D) reconstruction of M. tuberculosis iniA oligomers. (A) 2D crystals of hexameric MTB iniA. Inset: Projection of hexameric iniA. (B) Surface representation of 3D reconstruction of the predominant iniA oligomer obtained from single particle analysis shows C6 symmetry with threshold at 438 kDa. Reprinted from Ref. 20 with permission.