jmbReview Role of folP 1 and folP 2 Genes in the Action of Sulfamethoxazole and Trimethoprim Against Mycobacteria

Tuberculosis (TB) is a chronic disease caused by Mycobacterium tuberculosis (Mtb). The emergence of multidrug resistance (MDR), defined as resistance to at least the two main first-line anti-TB drugs, rifampicin and isoniazid; extensively drug resistance (XDR), defined as MDR strains that are also resistant to a fluoroquinolone and at least one second-line injectable agent such as amikacin, kanamycin (KAN), or capreomycin; and the more severe totally drug resistance (TDR), defined as Mtb strains resistant to all firstand second-line anti-TB drugs, is an urgent medical and public health concern, as the available anti-TB drugs exhibit limited efficacy [20, 26]. Development of new drugs is time-consuming, difficult, and expensive. However, if already existing clinically established effective drugs could be used for treatment of TB, then faster and cheaper drug development coupled with effective TB management would be attained. Sulfamethoxazole (SMX) and trimethoprim (TMP) are such potential candidates for TB treatment, having been used in drug regimens for the treatment of various bacterial infections of the respiratory, urinary, and gastrointestinal tracts for more than 40 years [1, 10]. TMP and SMX target successive steps of the folate biosynthesis pathway. SMX inhibits the dihydropteroate synthase (DHPS) activity, which catalyzes the addition of dihydropterindiphosphate to p-aminobenzoic acid (PABA), a structural analog of SMX. The product of DHPS, 7,8-dihydropteroate (DHP), reacts with glutamate to form dihydrofolate (DHF), which is reduced to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR), the target of TMP (Fig. 1). Bacteria, fungi, and plants synthesize folate de novo, but mammals lack DHPS and therefore cannot produce folate. THF is an essential co-factor involved in the transfer of a one-carbon unit and is implicated in the biosynthesis of purines and pyrimidines and in the biosynthesis and catabolism of some amino acids. The combination of TMP and SMX Received: March 16, 2015 Revised: April 20, 2015 Accepted: April 21, 2015