Gonorrhea is the second most commonly reported sexually transmitted infection (STI), with tens of millions of cases annually. In the United States alone, more than 600,000 cases are reported each year. If gonorrhea is left untreated, it can lead to severe reproductive health problems such as infertility and pelvic inflammatory disease in both women and men. Infection also increases the risk of HIV infection, and if the pathogen spreads from the genitals and throat to other parts of the body, it can damage the heart and cause meningitis and sepsis. The main challenge in controlling the disease more effectively lies in the capacity of the causative pathogen. gonorrheadue to the rapid development of resistance to newly available antibiotics.
Two new oral antibiotics, including zoliflodacin and gepotidacin, have recently been approved for the treatment of uncomplicated urogenital gonorrhea. These are the first completely new class of antibiotics developed to fight infections in more than 30 years. However, if these two antibiotics become widely used, it is almost certain that pathogens will eventually develop significant resistance to them. We have seen cycles of resistance development occur within just 5 to 10 years after the deployment of first-line drugs, and it has repeated itself over and over again. To win this continuing arms race, we will develop new antibiotics to fill our pipeline. ”
Melis Anahtar, MD, Ph.D., Physician Scientist, Associate Director, Clinical Microbiology Laboratory, Massachusetts General Hospital (MGH)
Now, a new study has been published scientific translational medicine A research team from the Wyss Institute at Massachusetts Institute of Technology and Harvard University, led by Wyss Institute core faculty member Dr. James Collins, and the Broad Institute of Massachusetts Institute of Technology and Harvard University, led by Anatal, Jacqueline Valeri, and Majid Modareshi, is proposing an exciting new strategy that could identify new compounds that can be further developed with high selectivity for antibiotic therapy. gonorrhea. The researchers initially hypothesized that entirely new chemical structures with antimicrobial activity could dramatically reduce the likelihood that antimicrobial resistance would develop because they could also target unusual cellular pathways in pathogens, and that deep learning-based antimicrobial discovery approaches could take the lead in identifying these structures.
“We have reached a critical point where a vast chemical space has opened up in which billions of compounds with well-defined structures can be synthesized. This converges with the rapidly evolving capabilities of machine learning, allowing us to explore that space with very specific biological activities in mind, such as much-needed new antimicrobial activities,” said senior author Collins. “This research builds on a body of research in our lab that focuses on leveraging artificial intelligence to fight infectious diseases. gonorrhea to help address the growing crisis of antimicrobial resistance against this rapidly evolving pathogen. ” Mr. Collins also said, Termeer MIT Professor of Medical Engineering and ScienceHe is also a member of the Broad Institute at MIT and Harvard University.
Building a machine learning pipeline
To lay the foundation for their approach, the team first tested the ability of 38,650 small molecules to inhibit proliferation. gonorrhea We analyzed data from laboratory assays and used this dataset to train a predictive deep learning model. They validated that the model could identify potential antimicrobial-like molecules with chemical structures that differ from common antibiotics.
After gaining confidence in the model’s ability to find “hidden gems” with anti-gonococcal activity, they used the AI model to virtually screen a much larger library of approximately 6 million compounds. This resulted in 213 candidates that were further validated. After a series of growth inhibition and antimicrobial resistance assays, as well as cell biological assays to exclude compounds with unwanted toxicity, they Strong efficacy against multidrug resistance gonorrhea The strain itself causes resistance at very low frequencies.
“Using proteomics methods, we succeeded in identifying the target of a most promising compound called A1, a so-called aminothiazole compound with hitherto undescribed antigonococcal activity. It specifically binds to and inhibits the key enzyme alanine racemase. gonorrhea “We used genetic tools to validate A1’s alanine racemase specificity and are currently investigating how exactly A1 inhibits its enzymatic activity.” Multiple existing antibiotics inhibit the cell wall biosynthesis process in pathogenic bacteria, but specifically targeting alanine racemase with small molecules is a novel mechanism uncovered by the research team, Anatal said.
from in silico to alive
As a next translational step, the research team investigated whether their compounds could exert anti-gonococcal activity in the physiological tissue environment of the vagina where gonococcal infections are present. gonorrhea It is done frequently. Working with the group of Wyss founding director and co-author Donald Ingber, MD, who had previously developed a microfluidic organ-chip model of the human vagina, they demonstrated that their first compound, MP20, significantly reduced pathogen titers after being introduced into the device and interacting with vaginal epithelial cells. In addition, in a mouse vaginal infection model inoculated intravaginally, gonorrhea For bacteria, treatment with the second compound A1 five times over 24 hours significantly reduced pathogen concentrations compared to the antibiotic-free control.
“While our observations with A1 are promising, further validation and hit-to-lead optimization through medicinal chemistry and other efforts are required before it becomes a clinically relevant antibiotic for the treatment of gonorrhea,” Anatal said. “However, our deep learning-enabled discovery pipeline has the potential to screen much broader, ultra-large make-on-demand chemical libraries to identify unexpected compounds as a new starting point for antibiotic development programs focused on gonorrhea.”
“This work by Jim Collins and his team once again demonstrates the enormous power of AI, combined with high-quality biological datasets, in discovering potential therapeutic compounds that are otherwise completely out of reach. It also shows how the Wyss Institute is seamlessly integrating important advances in AI with human-relevant models, in this case the human vaginal chip,” said co-corresponding author Ingber, MD. who is too Judah Folkman Professor of Vascular Biology Harvard Medical School and Boston Children’s Hospital, and Hansjörg Wyss Professor of Bioinspired Engineering Completed Harvard University John A. Paulson School of Engineering and Applied Sciences.
Other authors of the study include Aarti Krishnan, Nina Donghia, Samantha Palace, Erica Zheng, Aakanksha Gulati, Alicia Jorgenson, Abidemi Junaid, Parijat Bandyopadhyay, Andreas Luttens, Krishna Suresh, Paige Edwards, Felix Wong, Yu Zhang, Danilo Ritz, Margaux Gaboleau, Edmund Loh, Massimiliano Gaetani, Marie-Stéphanie Astgen, Amir Ata Saei, and Jonathan Grado.
sauce:
Wyss Institute for Bioinspired Engineering, Harvard University
Reference magazines:
Key, Minnesota; others. (2026). Discovery of antibiotics effective against infectious diseases using deep learning gonorrhea. scientific translational medicine. DOI: 10.1126/scitranslmed.ads4699. https://www.science.org/doi/10.1126/scitranslmed.ads4699
