Mannosides, small-molecule drugs that contain a mannose sugar group, may be able to treat and prevent urinary tract infections (UTIs), without inducing antibiotic resistance. Bacteria that cause UTIs often develop resistance to antibiotics, making those medications less effective. James W. Janetka and Scott J. Hultgren of Washington University School of Medicine, in St. Louis, and coworkers synthesized orally available mannosides active against uropathogenic bacteria and are optimizing them to improve their drug properties (Sci. Transl. Med., DOI: 10.1126/scitranslmed.3003021). The mannosides block the bacterial cell-surface receptor FimH, which bacteria use to interact with bladder epithelial cells to cause infection. In mice with chronic UTIs, the mannosides eliminated uropathogenic bacteria more effectively than did standard antibiotic treatments. The mannosides also work effectively with traditional antibiotics, and healthy mice treated with them don’t get infections. Bacteria typically develop resistance by pumping drug molecules out of their cells and mutating target proteins. But the mannosides function extracellularly, and mutating FimH could eliminate bacterial infectivity, making the development of resistance less likely than with standard antibiotics.