Conjugate attacks Gram-negative bacteria

Abstract

A new drug conjugate tricks Gram-negative bacteria into succumbing to an antibiotic that usually works only against Gram-positive bacteria. Gram-negative bacterial infections are tough to treat because the microbes have an extra outer membrane that is hard for antibiotics to traverse. And the ones that do get in are usually pumped right back out by the cells. To kill these hardy bacteria, Marvin J. Miller and coworkers at the University of Notre Dame have put a twist on a type of drug conjugate called a sideromycin. Such combinations usually consist of a siderophore—a chelating agent bacteria use to grab and collect iron from their surroundings—connected to an antibiotic. Usually there’s only one antibiotic attached, but Miller’s team adds a second one. Their synthetic sideromycin includes a siderophore, a cephalosporin, and an oxazolidinone (J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.8b00218). The siderophore gets a bacterium to take up the conjugate. Then the