Macrolide antibiotic action, resistance, and tolerance, and approaches to improve their activity against Gram-negative bacteria.

Macrolide antibiotics inhibit bacterial translation and are characterized by the presence of a macrocyclic lactone ring. First discovered as natural products of Streptomyces species, the potency of macrolide antibiotics against a diverse swath of bacterial pathogens has inspired continued efforts to develop semisynthetic derivatives with enhanced efficacy. Often used to treat community-acquired pneumonia, sexually-transmitted diseases, and gut infections, macrolides constitute one of the most commonly prescribed out-patient antibiotic classes in the world. However, those clinical successes have been tempered by the prevalence of macrolide resistance, observations of tolerance, and limited activity against many Gram-negative bacteria. Here, we review the macrolide antibiotic class by summarizing their discovery, biosynthesis, mechanism of action, and causes of failure, which include resistance and tolerance. We then discuss recent work that seeks to identify adjuvant compounds that could be delivered with macrolides to extend their spectrum of activity to more Gram-negative species, including those with multidrug-resistant strains.