Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis.
نویسندگان
چکیده
Folate biosynthesis is an established anti-infective target, and the antifolate para-aminosalicylic acid (PAS) was one of the first anti-infectives introduced into clinical practice on the basis of target-based drug discovery. Fifty years later, PAS continues to be used to treat tuberculosis. PAS is assumed to inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis by mimicking the substrate p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors of DHPS inhibited growth of M. tuberculosis only weakly because of their intracellular metabolism. In contrast, PAS served as a replacement substrate for DHPS. Products of PAS metabolism at this and subsequent steps in folate metabolism inhibited those enzymes, competing with their substrates. PAS is thus a prodrug that blocks growth of M. tuberculosis when its active forms are generated by enzymes in the pathway they poison.
منابع مشابه
Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance.
para-Aminosalicylic acid (PAS) entered clinical use in 1946 as the second exclusive drug for the treatment of tuberculosis (TB). While PAS was initially a first-line TB drug, the introduction of more potent antitubercular agents relegated PAS to the second-line tier of agents used for the treatment of drug-resistant Mycobacterium tuberculosis infections. Despite the long history of PAS usage, a...
متن کاملpara-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis.
para-Aminosalicylic acid (PAS) is one of the antimycobacterial drugs currently used for multidrug-resistant tuberculosis. Although it has been in clinical use for over 60 years, its mechanism(s) of action remains elusive. Here we report that PAS is a prodrug targeting dihydrofolate reductase (DHFR) through an unusual and novel mechanism of action. We provide evidences that PAS is incorporated i...
متن کاملMolecular genetics of para-aminosalicylic acid resistance in clinical isolates and spontaneous mutants of Mycobacterium tuberculosis.
The emergence of Mycobacterium tuberculosis resistant to first-line antibiotics has renewed interest in second-line antitubercular agents. Here, we aimed to extend our understanding of the mechanisms underlying para-aminosalicylic acid (PAS) resistance by analysis of six genes of the folate metabolic pathway and biosynthesis of thymine nucleotides (thyA, dfrA, folC, folP1, folP2, and thyX) and ...
متن کاملMechanisms involved in the resistance of Mycobacterium tuberculosis to para-aminosalicylic acid.
That para-aminobenzoic acid antagonizes competitively the inhibitory effect of paraaminosalicylic acid on the growth of Mycobacterium tuberculosis is well known. In a previous communication (Hedgecock, 1956) it was reported that inhibition of M. tuberculosis (strain H37Rv) by para-aminosalicylic acid was reversed noncompetitively by methionine and biotin when the concentration of the inhibitor ...
متن کاملGenome sequencing reveals novel deletions associated with secondary resistance to pyrazinamide in MDR Mycobacterium tuberculosis.
OBJECTIVES Detection of pyrazinamide resistance in Mycobacterium tuberculosis isolates presents significant challenges in settings with no dominant clonal lineages, such as Australia. We assessed the utility of WGS versus standard PCR amplification assays for the characterization of pyrazinamide resistance in MDR-TB isolates identified in New South Wales, Australia, over an 8 year period. MET...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Science
دوره 339 6115 شماره
صفحات -
تاریخ انتشار 2013