University of Oklahoma biochemists are leading a $5.3 million, five-year National Institute of Allergy and Infectious Diseases-funded project to address the growing threat of drug-resistant bacteria, responding to what the researchers term “the human cost of inaction” exemplified by recent fatal foodborne outbreaks.
With experts predicting antimicrobial resistance could claim up to 2 million lives annually by 2050 without new treatments, the research team aims to develop innovative methods for delivering life-saving medications directly into resistant pathogens.
The Antimicrobial Resistance Threat
“Humans typically coexist with bacteria—we depend on them for gut health and immunity,” explained Professor Valentin Rybenkov, co-principal investigator. “While we have defenses against harmful bacteria, sometimes these defenses fail. When bacterial growth outpaces our immune system’s capacity to eliminate them, we need antibiotics.”
Unfortunately, antibiotic resistance is increasing globally at an alarming rate of up to 15% annually, with the World Health Organization reporting that one in six bacterial infections now demonstrates resistance, rising to nearly one-third in Southeast Asia and the Eastern Mediterranean.
Scientific Approach and Pathogen Focus
The research targets Gram-negative bacteria (GNB), pathogens that have evolved sophisticated defense mechanisms including dual cell membranes and enhanced “efflux” pumps—protein structures that actively expel toxins from bacterial cells.
These defenses make current antibiotic classes increasingly ineffective. To identify vulnerabilities in GNB’s armor, the team is screening approximately 2,000 chemicals and compounds against hundreds of efflux pump variants to identify candidates capable of penetrating resistant pathogens like Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii.
Innovative Methodology and Technical Strategy
“Think of a boat with small holes,” said lead investigator Dr. Zgurskaya. “Without intervention, it sinks slowly but surely. But if the boat has pumps, it clears any accumulation. Gram-negative bacteria have similar mechanisms. Our job as researchers is to find ways to create holes while disabling the pumps.”
The team combines laboratory experimentation with machine learning to analyze penetration capabilities across chemical libraries eventually numbering in the hundreds of thousands, identifying patterns that could lead to more effective treatments.
Collaborative Network and Research Integration
The OU team collaborates with an interdisciplinary network including:
- Professor Paolo Ruggerone (University of Cagliari, Italy) – physics and computational modeling
- Professor John Walker (St. Louis University) – pharmacology and physiology
- ArrePath (Princeton, New Jersey) – drug discovery expertise
This partnership leverages diverse expertise to accelerate identification of promising compound candidates and their mechanisms of action.
Future Directions and Public Health Impact
“There’s no simple way to predict which molecules can penetrate cell membranes,” noted Rybenkov. “Artificial intelligence helps us navigate this complexity.”
Beyond addressing antibiotic overuse—frequently cited as the primary driver of resistance—the research acknowledges bacterial evolution as a natural process requiring sophisticated scientific countermeasures. The project represents a critical component of global efforts to maintain effective treatments against dangerous pathogens that increasingly view humans as “just food” in the evolutionary struggle between host and pathogen.
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