نقش جهش های ژن pncA W68R و W68G در مقاومت پری زینامید Role of pncA gene mutations W68R and W68G in Pyrazinamide resistance

Introduction Among humans, Tuberculosis (TB) which, spreads by aerosols is one of the leading cause of infection related deaths. Tuberculosis (TB) manifests upon infection by its bacterial causative agent, Mycobacterium tuberculosis (Mtb) [Organization, 2015]. As on 2015, 10.4 million individuals were infected with TB which led to the death of 1.5 million individuals around the world. One of the major reasons for this alarming rise in spread of TB is due to the emergence of drug resistant strains [Stehr et al., 2015]. In 2015, > 4.7 million new cases of Multi drugresistant tuberculosis (MDR-TB) were detected which, resulted in about 250000 deaths [Organization, 2016]. Moreover, 9.7% people with MDR-TB were reported to have Extensively drug-resistant tuberculosis (XDR-TB) [Organization, 2015]. This burgeoning phenomenon of antibiotic resistance is believed to be the result of several point mutations in specific key resistance genes [Chan et al., 2007]. Thereby there is an urgent need to combat this disease. The World Health Organization recommended protocol of treatment for new TB patients is DOTS (directly observed treatment, short-course), which is a six months course involving four first-line drugs; isoniazid, rifampin, pyrazinamide and ethambutol [Organization, 2015]. However, this therapy is marred by the poor efficacy of first line anti-tubercular drugs and high toxic side effects of second line drugs [Dooley et al., 2012]. It is due to the fact that Mtb is impervious to numerous anti-toxins produced by other bacteria due to the presence of highly hydrophobic cell envelope acting as a permeability barrier [Cole et al., 1998]. Pyrazinamide (PZA), a derivative of nicotinamide, has the unique ability to kill persistent bacilli which resides in the low pH environment of the host macrophages, hence reducing the period of chemotherapy [Gu et al., 2015; Mitchison, 1985]. Nicotinamide was reported to have activity against Mycobacterium in animal models by Chorine in 1945 [Ryan, 1993]. PZA was identified as an active analog of nicotinamide by direct testing on a mouse model of TB infection [Malone et al., 1952; McKenzie et al., 1948; Solotorovsky et al., 1952]. Its role as an anti-tuberculosis drug was discovered in 1952 [Yeager et al., 1952]. In 1996, it was confirmed that pncA gene was strongly associated with intrinsic PZA resistance in Mtb [Scorpio and Zhang, 1996] and in 1997 it was found that mutations in pncA gene constituted the significant reason behind PZA resistance [Scorpio and Zhang, 1996].