Infections caused by highly drug resistant Gram-negative bacteria such as K. pneumoniae and P. aeruginosa cause high mortality infections. Treatment options are limited, relying on ‘last resort’ historical agents with known toxicity liabilities such as the polymyxins. 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.
This talk will discuss our research program focused on developing octapeptin analogs (OPX) as a new class of antibiotics. This program recently received substantial funding from global agency CARB-X (the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator), the first to an Australian organisation, and the first to any university in the world [1].
OPX retain activity against polymyxin-resistant Gram-negative bacteria, despite their structural similarity [2]. Mode of action studies, employing surface plasmon resonance, membrane probe assays, and fluorescently-labelled analogues prepared for membrane localization and permeabilisation studies, highlighted subtle variations in membrane interactions and permeability between the classes. A structure-activity-relationship campaign examined substituent effects and identified compounds with improved properties. Analogs were profiled for MIC potency, cytotoxicity and nephrotoxicity using primary human kidney cells. Promising compounds were advanced into in vivo mouse studies, including infection efficacy models, pharmacokinetic studies, and nephrotoxicity models.
We have also begun to investigate the application of OPX as potentiators (OPX-P), ‘adjuvants’ that help restore the activity of existing antibiotics that have become obsolete due to the development of resistance.
The octapeptins show promising activity against polymyxin- resistant MDR Gram-negative bacteria. Importantly, they appear to be much less susceptible to development of resistance than the polymyxin. Given the paucity of Gram-negative candidates, the octapeptins are a rare beacon of light in the fight against antimicrobial resistance.