LAUSR

ABSTRACT Introduction: The octapeptins are a family of cyclic lipopeptides first reported in the 1970s then largely ignored. At the time, their reported antibiotic activity against polymyxin-resistant bacteria was a curiosity. Today, the advent of widespread drug resistance in Gram-negative bacteria has prompted their ‘rediscovery.’ The paucity of new antibiotics in the clinical pipeline is coupled with a global spread of increasing antibiotic resistance, particularly to meropenem and polymyxins B and E (colistin). Areas covered: We review the original discovery of octapeptins, their recent first chemical syntheses, and their mode of action, then discuss their potential as a new class of antibiotics to treat extensively drug-resistant (XDR) Gram-negative infections, with direct comparisons to the closely related polymyxins. Expert commentary: Cyclic lipopeptides in clinical use (polymyxin antibiotics) have significant dose-limiting nephrotoxicity inherent to their chemotype. This toxicity has prevented improved polymyxin analogs from progressing to the clinic, and tainted the perception of lipopeptide antibiotics in general. We argue that the octapeptins are fundamentally different from the polymyxins, with a disparate mode of action, spectra of action against MDR and XDR bacteria and a superior preclinical safety profile. They represent early-stage candidates that can help prime the antibiotic discovery pipeline.