Chemists Help Crack Code Behind Tuberculosis Drug Resistance
University of Virginia chemists have contributed to a major international study identifying chemical features that help drugs slip past a key defense of tuberculosis bacteria, a discovery that could speed development of shorter, more effective treatments for the world's deadliest infectious disease.
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, kills more than 1 million people annually, and current treatments require at least four months of antibiotics. Researchers have long suspected that the bacterium’s outer membrane’s resistance to certain drugs helps explain why treatment takes so long, but the specific chemical characteristics of that membrane — known as a mycomembrane — that allow some molecules to pass through while blocking others had remained unclear.
Marcos Pires, a professor in the College and Graduate School of Arts & Science's Department of Chemistry and one of the study's authors, worked with chemistry graduate and undergraduate researchers Zichen Liu, Rachita Dash and Ananya Naick as part of a multi-institution team that screened more than 1,500 chemically tagged molecules to see which could cross the mycomembrane. The team, which also included researchers from the University of Massachusetts Amherst, Lehigh University, Rutgers University and the Scripps Research Institute, used a technique called PAC-MAN, developed in part by the Pires lab, that attaches a chemical tag to molecules and tracks whether they've slipped past the mycomembrane.
By combining that screening data with machine learning, the researchers built a predictive model, dubbed MycoPermeNet, that allowed them to identify strong predictors of both permeability and antibacterial activity. The team confirmed the model's predictions by redesigning three separate drug candidates to improve their ability to breach the bacterial defense.
The findings offer drug developers a framework for modifying existing tuberculosis drugs or designing new ones with the capacity for better cell penetration, potentially shortening treatment times and improving outcomes for patients worldwide.
The research, published in the journal Nature Microbiology, underscores the growing role of UVA's chemistry department in tackling global health challenges through interdisciplinary collaboration, pairing laboratory chemistry with computational modeling to address problems that have long been obstacles to drug discovery.
