A novel antibiotic class targeting a major global pathogen and threat to human health has been discovered by scientists from Roche and Harvard University (Cambridge, MA, US).
In two studies published in Nature, the authors demonstrate that the new class of drug candidates can effectively target Carbapenem-resistant Acinetobacter baumannii (CRAB), which is high on the World Health Organization (WHO) list of priority pathogens.
One of the molecules, called zosurabalpin, killed multiple resistant strains of A. baumannii in culture, and, in mice, a strain resistant to all available antimicrobials. The first clinical-trial results for the compound are expected this year.
“New antibiotics directed against the world’s highest priority bacteria, like Acinetobacter baumannii, require novel development paths. Importantly, regulatory guidelines facilitate this, allowing us to use highly translatable animal model data to complement leaner clinical trials in support of registration,” said Michael Lobritz, Head of Infectious Diseases, Roche Pharma Research and Early Development (pRED).
Unlike broad-spectrum antibiotics, the potential new antibiotic is specific to carbapenem-resistant A. baumannii. It inhibits the LptB2FGC complex, the machinery that assembles the outer membrane of gram-negative bacteria.
The researchers concluded: “This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development.”1
The second molecule, murepavadin, also targets Gram-negative pathogens through lipopolysaccharide transport (Lpt) proteins, though it yet to enter human trial.2
The discovery follows the news that MIT researchers have identified a new class of antibiotic candidates that can kill another deadly bacteria, methicillin-resistant Staphylococcus aureus (MRSA).
Low market incentives
In July 2023, a report by University of Queensland (UQ) researchers warned that a global crisis of antibiotic resistance is inevitable.
Despite the threat, no new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years. The lack of innovation in this area has been blamed on low market incentives for companies to invest in antibiotic research.
In a DDW interview, Christopher Reid, Professor of Biological and Biomedical Sciences at Bryant University, in Rhode Island, US, explained further: “Only about one in five infectious disease drugs that reach the initial phase of human testing will receive approval from the FDA. Developing antibiotics to treat highly resistant infections is particularly challenging as only a small number of patients contract these infections and meet the requirements to participate in traditional clinical trials. Finally, the current market incentives for investing in antibiotic development deter investment in this area as creeping resistance issues will shorten patent lifetimes.”
Government incentives provide one solution. In 2019 the UK government published a 20-year vision for tackling antimicrobial resistance (AMR) and will publish a new five year National Action Plan for AMR in early 2024. Last year saw significant government investment in initiatives to tackle AMR, including up to £210 ($267) million for the Fleming Fund and £39 ($48) million through the Global AMR Innovation Fund (GAMRIF).
On 3 January the House of Commons’ Science, Innovation and Technology Committee published a report examining the antimicrobial potential of bacteriophages as a possible solution to the problem of AMR.3
Diana Spencer, Senior Digital Content Editor, DDW