Drug resistant and persistent tuberculosis: Mechanisms and drug development

Mycobacterium tuberculosis is a particularly successful pathogen that latently infects about one third of world population (about two billion people). Despite the availability of chemotherapy and BCG vaccine, tuberculosis (TB) remains a leading cause of infectious morbidity and mortality, causing about nine million new cases and nearly 1.5-2 million deaths annually [142]. The increasing emergence of drug-resistant TB, especially multidrug-resistant TB (MDR-TB) (resistant to at least isoniazid [INH] and rifampin [RIF]) and more recently extensively drug-resistant TB (XDR-TB), has caused a great deal of concern. XDR-TB is defined as MDR-TB plus additional resistance to two major second-line drugs fluoroquinolones and one of the three injectables (capreomycin, kanamycin, and amikacin) [141]. The recent outbreak of XDR-TB in South Africa where 52 of 53 HIV-positive individuals infected with XDR-TB died in an average of 16 days is particularly alarming [44]. There are about 500,000 new cases of MDR-TB and 40,000 XDR-TB cases a year [141]. The TB situation is further complicated by the spread of HIV pandemic worldwide, which weakens the host immune system and allows latent TB to reactivate or makes the person more susceptible to reinfection with drug susceptible and even drug-resistant strains [123]. It is estimated that of about 40 million people infected with HIV, one third are also co-infected with the tubercle bacillus. These individuals are 20-30 times more likely to develop TB and have five times higher mortality than those without HIV [95]. The current TB control regimen is seriously undermined by MDR/XDR-TB and HIV infection, which is a lethal combination and presents significant challenges for effective TB control.