Nat. Microbiol. 2, 17028 (2017)

Credit: SHAWN FRENCH

Infections of Gram-negative bacteria can be particularly difficult to treat, as the bacteria's outer membranes make them impervious to the antibiotics that would kill their Gram-positive counterparts. To identify compounds that could overcome this innate resistance, Stokes et al. screened a collection of previously approved small-molecule drugs for their ability to perturb the outer membrane of Escherichia coli in a nonlethal manner. The results of this screen identified pentamidine, an antiprotozoal drug that induced rippling in the E. coli outer membrane visible by atomic force microscopy, through an interaction with lipopolysaccharide (LPS). Co-treatment with pentamidine made E. coli susceptible to rifampicin, novobiocin, and erythromycin, which are normally effective only against Gram-positive strains. Pentamidine also synergized with rifampicin against a variety of Gram-negative species, including strains of E. coli and Klebsiella pneumoniae harboring mcr-1, which confers resistance against last-line antibiotics such as colistin. In a mouse model, co-treatment with pentamidine and novobiocin cleared infections of Acinetobacter baumanii, including nearly all cases exhibiting colistin resistance. The use of pentamidine or other similar compounds could give new life to antibacterial drugs facing strains exhibiting either innate or acquired resistance. Furthermore, the fact that pentamidine is already approved for use in humans could smooth its path toward approval for additional uses.