Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) is awarding US$853k to UNSW Sydney to support the development of synthetic darobactin analogues, a new class of antibiotic designed to kill multidrug-resistant Gram-negative bacteria.
UNSW, in partnership with Donum Therapeutics, is applying structure-guided chemistry to re-engineer darobactin into a more potent molecule suitable for treating patients. Darobactin is a naturally occurring peptide antibiotic that was first reported in 2019. It was discovered in Photorhabdus bacteria associated with insect-hunting nematodes as part of bioprospecting efforts to identify new antibiotics from natural sources.
Darobactin kills Gram-negative bacteria by binding to BamA, a novel antibiotic target found in the bacterial outer membrane and involved in outer membrane biogenesis. Because no antibiotics on the market target BamA, darobactin retains activity against multidrug resistant isolates and shows no cross-resistance with existing antibiotic classes.
Synthetic platform
CARB-X will support efforts to advance UNSW’s synthetic darobactin platform towards further understanding its potential to deliver potent broad-spectrum Gram-negative antibiotics.
“Cross resistance is one of the greatest treatment challenges posed by multidrug-resistant bacteria. When a single genetic change can render an entire class of medications ineffective, doctors can quickly run out of options to treat serious infections, and patient outcomes suffer. New antibiotic classes, like darobactin, can introduce new ways of targeting bacteria and may avoid cross resistance with existing antibiotics,” said Richard Alm, PhD, Chief of Research and Development at CARB-X. “This award reflects our commitment to supporting innovative approaches aimed at treating some of the most dangerous bacterial infections facing patients worldwide.”
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“This support will enable UNSW and Donum Therapeutics to advance the discovery of a new class of antibiotics — reimagining nature’s own molecules through chemistry in a bid to treat drug-resistant infections that current therapies can no longer defeat,” said Principal Investigator Dr Bryson Hawkins from UNSW Medicine & Health.
Recent estimates project that AMR could cause 39 million deaths over the next 25 years. However, a regular release of new, potent antibiotics targeting Gram-negative bacteria could save 11.1 million lives, especially in low-and-middle-income countries (LMICs) in regions including South Asia, Southeast Asia, East Asia and Oceania, and sub-Saharan Africa.
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