ABSTRACT
para-Aminosalicylic acid (PAS) is one of the oldest antitubercular drugs, and first entered clinical use in 1944 (Lehmann, 1946). PAS (chemical structure shown in Figure 131.1), a structural analog of the folate precursor para-aminobenzoic acid (PABA), is a prodrug that is activated within the Mycobacterium tuberculosis folate biosynthetic pathway and ultimately inhibits dihydrofolate reductase (DHFR) (Chakraborty et al., 2013; Zheng et al., 2013; reviewed in Minato et al. 2015). Early multidrug therapy regimens including combinations of PAS, streptomycin, and isoniazid resulted in a significant increase in tuberculosis (TB) cure rates relative to mono- and dual therapy regimens (reviewed in Fox, 1979). Until the mid-1960s PAS was a standard component of the first-line multidrug regimen for the treatment of TB. However, PAS treatment was commonly associated with gastrointestinal disturbance and other severe adverse reactions, and was replaced with a better-tolerated companion agent, ethambutol (Ferebee et al., 1966). A subsequently developed gastroresistant delayed-release granule formulation of the free base of PAS (GR-PAS or Paser) has shown significantly reduced gastrointestinal disturbance (Peloquin et al., 1994; Peloquin et al., 1999). In response to the recent global spread of multidrug-resistant (MDR; resistant to isoniazid and rifampin) and extensively drug-resistant (XDR; resistant to isoniazid, rifampin, fluoroquinolones, and any second-line injectable drug) strains of M. tuberculosis, PAS has re-entered antitubercular drug regimens as an important second-line agent (Donald and Diacon, 2015). Structure of <italic>para</italic>-aminosalicylic acid. https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781315152110/08d8042d-9481-4a8d-8c27-9bd589f6de6b/content/fig131_1.tif" xmlns:xlink="https://www.w3.org/1999/xlink"/>
