Researchers have discovered a new class of antibiotic that can kill some of the most deadly drug-resistant bacteria, including a bacterium on the World Health Organization’s (WHO) priority list of concerning drug-resistant pathogens. This breakthrough offers new hope in the fight against antimicrobial resistance.
Discovery of zosurabalpine provides potent weapon against superbugs
A team at MIT has identified a new antibiotic compound called zosurabalpine which acts against Acinetobacter baumannii, a dangerous superbug that has developed resistance to all known antibiotics. Zosurabalpine belongs to a new class of antibiotics known as macrocyclic peptides.
In early testing on mice with lung infections, a single dose of zosurabalpine completely eliminated the bacteria within 24 hours and saved 80-100% of animals from dying. The antibiotic was also effective in combating several other types of drug-resistant pathogens.
“This compound looks incredibly potent in animal models. That’s not something that I would have expected when we started this project,” says Professor Richard Novicki, who co-led the research team.
The discovery is significant because A. baumannii has become a leading hospital-acquired infection worldwide, causing deadly pneumonia and bloodstream infections that are almost impossible to treat due to extensive drug resistance.
“For the last 10 or 15 years, A. baumannii has been a big worry amongst hospital specialists because it causes very severe bloodstream and lung infections but has basically become resistant to all antibiotics,” says Novicki.
AI helps pinpoint promising antibiotic candidate
The researchers used a machine learning model trained on over 2,500 compounds to predict which drug candidates have antibiotic properties. This artificial intelligence (AI) model singled out zosurabalpine as the most promising antibiotic lead.
“The AI tool greatly accelerates the identification of promising antibiotics that we should further pursue for antibiotic development,” says Novicki. “If we didn’t have this computational assistance, it would be incredibly difficult to search through such an enormous chemical space.”
New antibiotic blocks membrane function in bacteria
Unlike other antibiotics that penetrate the bacterial cell wall to interfere with critical functions inside, zosurabalpine destroys bacteria by directly attacking the cell membrane. It binds to negatively charged parts of the membrane using its own positively charged regions, disrupting membrane integrity and causing leakage that quickly kills bacteria.
“Zosurabalpine has a completely different mechanism than any other antibiotic,” explains Novicki. “It acts on the cell membrane surface rather than penetrating inside the cell, which appears to contribute to its ability to overcome antibiotic resistance mechanisms.”
This membrane-targeting mechanism gives zosurabalpine potency against a wide range of Gram-negative pathogens beyond A. baumannii, including other deadly superbugs on the WHO priority list such as carbapenem-resistant Enterobacteriaceae (CRE).
New incentives and funding needed to reinvigorate antibiotic pipeline
The exciting discovery comes amid growing fears that medicine is losing the race against rising antibiotic resistance, which threatens to make minor injuries and routine surgery potentially fatal.
Novel classes of antibiotics have not emerged for decades, as most major pharmaceutical companies abandoned making antibiotics due to lack of profitability compared to drugs that treat chronic conditions.
“The pipeline for new antibiotics has largely dried up over the past 30 years,” observes Dr. Amesh Adalja, Senior Scholar at Johns Hopkins Center for Health Security. “Zosurabalpine demonstrates that innovation is still possible but will require public policy attention in order to catalyze more private sector efforts.”
Many experts argue that new incentives and public funding models are urgently needed to stimulate research into novel antibiotics. Some possibilities include prizes, subscription-based payments rather than sales, or public-private partnerships that share costs and risks.
“The reward for making a new antibiotic should be commensurate with the enormous benefit new antibiotics provide to society,” says economist Lord Jim O’Neill, author of a UK government review on antimicrobial resistance. “We need a new commercial model so these life-saving medicines get developed sustainably.”
Next steps for developing new antibiotic into clinical use
The MIT researchers plan to continue optimizing zosurabalpine’s therapeutic properties and production process before starting clinical trials within the next two years.
“There is more work to do to translate this lab-based discovery into an actual antibiotic treatment for patients,” cautions Dr. Helen Boucher, Director of the Tufts Center for Integrated Management of Antimicrobial Resistance.
Key next steps are testing zosurabalpine’s efficacy and safety in humans through clinical trials, and scaling up cost-effective manufacturing.
Novicki aims to found a startup company and partner with larger pharmaceutical firms to advance zosurabalpine into a usable antibiotic product if trials succeed. “We hope to translate this compound into a drug that doctors can prescribe to save lives threatened by highly antibiotic-resistant bacterial infections.”
“The development of new antibiotics is crucial for preserving modern medicine, so investment in their research and production pipelines deserves to be a very high global priority,” emphasizes Adalja. “Antibiotic resistance poses an existential threat that we cannot afford to ignore.”
|Activity against key pathogens
|Disrupts bacterial membrane integrity
|Acinetobacter baumannii, carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa
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