ABSTRACT
I. Introduction Antifolates and hydroxynaphthoquinones are among the oldest known antimicrobial agents. The prototype antifolate was prontosil, discovered by Gerhard Domagk in the early 1930s. Prontosil proved to be a prodrug, activated by host metabolism into a sulfonamide. Various other sulfonamides were proven to be effective antimicrobials by the late 1930s. The first clue about their mechanism of action was the observation that p-aminobenzoic acid antagonized their antibacterial activity, published in 1940. In 1962, it was shown to act via the inhibition of dihydropteroate synthase (DHPS), an early enzyme in folate biosynthesis (reviewed in Ref. 1). Dapsone, a sulfone, also acts on this target and was first developed in the 1940s to treat leprosy [2].
