Sulfonamide resistance: mechanisms and trends

Sulfonamides were the first drugs acting selectively on bacteria which coul d be used systemically. Today they are infrequently used, in part due to wi despread resistance. The target of sulfonamides, and the basis for their se lectivity, is the enzyme dihydropteroate synthase (DHPS) in the folic acid pathway. Mammalian cells are not dependent on endogenous synthesis of folic acid and generally lack DHPS. Instead, they have a folate uptake system wh ich most prokaryotes lack. Laboratory mutants in the dhps(folP) gene can be easily isolated and show a trade off between sulfonamide resistance and DH PS enzyme performance. Clinical resistant mutants, however, have additional compensatory mutations in DHPS that allow it to function normally. In many pathogenic bacteria sulfonamide resistance is mediated by the horizontal t ransfer of foreign folP or parts of it. Clinical resistance in gram-negativ e enteric bacteria is plasmid-borne and is effected by genes encoding alter native drug-resistance variants of the DHPS enzymes. Two such genes, sul1 a nd sul2, have been sequenced and are found at roughly the same frequency am ong clinical isolates. Remarkably, the corresponding DHPS enzymes show pron ounced insensitivity to sulfonamides but normal binding to the p-aminobenzo ic acid substrate, despite the close structural similarity between substrat e and inhibitor. (C) 2000 Harcourt Pubslishers Ltd.