Optimisation of a membrane-targeting bicyclic heptapeptide for treatment of KAPE infections

Project title: Novel drugs against Gram-negative bacterial pathogens

New antibiotics are urgently needed against Gram-negative pathogens in the ‘KAPE’ group – Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter. A highly conserved chaperone-like protein, BamA (which is involved in the synthesis of essential outer membrane proteins) is an appealing target, which was considered undruggable by small molecules until recently.

However, the identification of Darobactin A, a natural product that selectively targets BamA, and the elucidation of the biosynthetic route to the bicyclic heptapeptide, has allowed the team at Justus-Liebig-University Giessen to make a number of modified lead compounds, which showed improved activity and successfully reduced bacterial loads of K. pneumoniae and P. aeruginosa in physiological models of lung infection. They have now teamed up with Infex Therapeutics, a clinical-stage anti-infectives development company, to accelerate the onwards development of the program.

The funding and support from PACE will allow the co-development team to continue these efforts. The primary objective will be optimisation of the lead structure using in vitro and in vivo profiling, with the aim of supporting nomination of a candidate for preclinical studies. The focus will be on developing a drug effective against complicated urinary tract infections, while also assessing efficacy against lower respiratory tract infections.

Success would result in a new class of antibiotics that target a range of multi-drug-resistant Gram-negative pathogens, and do not show cross-resistance to existing treatments. With the novel mode of action and favourable toxicity profile, such antibiotics should address unmet patient needs and be a highly effective option for treating life-threatening hospital-acquired infections.

Company bio:

Founded in 1607, Justus Liebig University Giessen (JLU) is a research university with a long-standing tradition which attracts around 25,700 students. Apart from the wide range of subjects on offer ‒ extending from classical natural sciences, law and economics, social and educational sciences to linguistics and cultural studies it offers a selection of life science subjects that is unique not only in Hesse: human and veterinary medicine, agricultural, environmental and nutritional sciences and food chemistry. The leading personae who carried out research and taught at JLU include a number of Nobel Prize winners, such as Wilhelm Conrad Röntgen (Nobel Prize for Physics in 1901) and Wangari Maathai (Nobel Peace Prize in 2004). Since 2006 JLU has been receiving continuous funding from German central and state governments in the Excellence Initiative and the Excellence Strategy.

Company bio:

Infex Therapeutics is a clinical-stage anti-infectives development company that acquires, develops and licenses innovative drugs to treat pandemic infections. They have expanded to develop a broader portfolio of new therapies to meet the rising burden of critical priority infectious disease. Based at Alderley Park in the North West of England, their work addresses unmet patient needs and will bring a new portfolio of drugs into clinical trials to treat patients suffering from life-threatening infections.