Infections caused by extensively-drug resistant (XDR) Gram-negative bacteria are an increasing threat to human health. The evolution of high levels of resistance is making the last-resort polymyxin lipopeptide antibiotics (colistin and Polymyxin B) obsolete, with alternate antibiotics urgently required. The octapeptins are naturally derived products, first reported in the 1970s, that are structurally similar to the polymyxins. They retain activity against polymyxin resistant isolates, but to date have been largely ignored.[1]
Intrigued by this observation, we initiated a research program to explore the potential of this class as a last resort therapy, and recently reported the first octapeptin synthesis, and confirmed its activity against polymyxin resistant clinical isolates.[2,3] The octapeptins retain activity against polymyxin-resistant Gram-negative bacteria, despite their structural similarity. Mode of action studies, employing surface plasmon resonance, membrane probe assays, and fluorescently-labelled analogues prepared for membrane localization and permeabilization studies, highlighted subtle variations in membrane interactions and permeability between the classes. An induced resistance study demostrates fundamental differences from the polymyxins, with rapid induction of high resistance by polymyxins, but not octapeptin C4, and no cross resistance between the two classes
An SAR campaign was undertaken to examine substituent effects and identify compounds with improved properties. Analogs were profiled for MIC potency, cytotoxicity and nephrotoxicity using primary human kidney cells. Advanced compounds were further assessed for PK/efficacy (mouse), and nephrotoxicity (rats). Promising compounds were advanced into in vivo mouse studies.
The octapeptins show promising activity against polymyxin- resistant MDR Gram-negative bacteria. Importantly, they induce resistance slowly. We have developed new analogs with improved in vitro activity and reduced nephrotoxicity, accompanied by efficacy in an in vivo mouse thigh infection model. Given the paucity of Gram-negative candidates, the octapeptins are a rare beacon of light in the fight against antimicrobial resistance.