Infections caused by multi drug-resistant (MDR) and extensively-drug resistant (XDR) Gram-negative bacteria are an increasing threat to human health. The evolution of resistance is nullifying the last-resort polymyxin lipopeptide antibiotics (colistin and Polymyxin B), with alternate antibiotics urgently required. The octapeptins, are a relatively unexplored family of natural product lipopeptides structurally related to the polymyxins. We have shown that the octapeptins (including improved analogues) retain activity against Polymyxin-resistant Gram-negative bacteria, accumulate resistance far more gradually, display less nephrotoxicity than the polymyxin’s, posses a good PK profile, and have efficacy in a mouse thigh infection model. Despite the exciting progress that has been made to develop improved octapeptin analogues the question remains; Is their potency as stand-alone antibiotic candidates the most promising use for these naturally derived Gram-negative antimicrobials? In the quest to develop alternative approaches to standard therapeutic treatments for hard to treat XDR Gram-negative bacterial infections many infectious disease researchers are searching for the ideal antibiotic adjuvants to potentiate the activity of clinically used drugs. Intrigued by this approach and our progress with improved octapeptin analogues, we began investigating the potential of our lead candidates (both in their full-length version and truncated) as antibiotic adjuvants, as an alternative to developing these lipopeptides as single drug leading therapies. Our preliminary studies show potent activity of our octapeptin analogues in partnership with ordinarily in-active antibiotics against XDR Gram-negative bacteria, including polymyxin resistant clinical isolates.