New mechanism disables antibiotic resistance and cross-protection in bacteria

A newly discovered mechanism renders antibiotic-resistant bacteria vulnerable by disabling both their individual resistance and a process known as cross-protection, the ability of resistant bacteria to shield nearby, otherwise sensitive strains. This occurs because resistant bacteria can degrade antibiotics in their surroundings, reducing drug levels and allowing other microbes to survive. By targeting this shared defense, researchers aim to restore the effectiveness of antibiotics, enabling them to eliminate not only resistant bacteria but also the susceptible microbes they protect.

This study, published today in the journal eLife, opens up new possibilities for treating resistant and polymicrobial infections associated with cystic fibrosis. Because similar bacterial survival mechanisms are found across many species, the findings may also inform the treatment of a broad range of antibiotic-resistant infections-marking a significant step forward in addressing the global challenge of drug resistance.

"Certain pathogens have developed resistance to nearly all available antibiotics. In some cases, they can also shield one another, making standard treatments far less effective," said lead author Nikol Kadeřábková, a research associate in the lab of Despoina Mavridou at The University of Texas at Austin's Department of Molecular Biosciences. "By targeting a protein-folding system, our research shows that both resistance and cross-protection can be inactivated, allowing conventional antibiotics to regain their effectiveness."

Kadeřábková led this research alongside Chris Furniss, a postdoctoral research fellow at Imperial College London in the United Kingdom.

This work was supported in part by the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health. Additional support was provided by the U.K. Medical Research Council, UT's Cockrell School of Engineering, the Fundação para a Ciência e a Tecnologia, I.P., the Welch Foundation, and the U.K. Biotechnology and Biological Sciences Research Council.

While most antimicrobial resistance research focuses on single pathogens grown in isolation, the majority of clinical infections contain multiple species that resist treatment in different ways. This coexistence gives rise to complex interactions, including cross-protection, which can further reduce the effectiveness of available therapies. To better reflect real-world conditions, Kadeřábková, Furniss and the rest of the team studied synthetic polymicrobial communities of Pseudomonas aeruginosa and Stenotrophomonas maltophilia, an approach that more closely mimics the challenges of treating cystic fibrosis-related lung infections.

P. aeruginosa is the most prevalent organism in cystic fibrosis lung infections, and treatment relies heavily on β-lactam antibiotics, a class that includes drugs such as penicillins and cephalosporins. In contrast, S. maltophilia is increasingly detected in cystic fibrosis microbiomes and is resistant to nearly all antibiotics, including β-lactams. Although multiple mechanisms contribute to this resistance, S. maltophilia primarily relies on the production of β-lactamases, enzymes that break down β-lactam antibiotics. These enzymes are highly efficient and can degrade antibiotics in the surrounding environment, effectively extending protection to nearby bacteria. This cross-protection not only shields other pathogens but has also been shown experimentally to promote the evolution of β-lactam–resistant P. aeruginosa strains, further complicating treatment.

To counter these interactions, the researchers targeted a protein-folding system that is essential for resistance enzymes to function. By disrupting this system, they aimed to sensitize both bacterial species to β-lactam antibiotics. To test their approach, the team used two complementary strategies: genetic modification and chemical inhibition.

The team found that deleting the protein-folding gene from bacterial genomes deactivated resistance enzymes and sensitized both P. aeruginosa and S. maltophilia to antibiotics. This confirmed that disrupting protein-folding mechanisms is a viable strategy for overcoming antibiotic resistance in these pathogens. They then showed that the same effect could be achieved using chemical inhibitors, demonstrating that antibiotic resistance can be reversed without genetic modification and highlighting a potential pathway for new drug development. Finally, in experiments using infected wax moth larvae and mixed bacterial communities, the researchers found that disrupting the folding system not only resensitized bacteria to treatment but also prevented one species from protecting another.

While our work so far has been conducted in the lab, it highlights a previously untapped vulnerability in some of the most stubborn antibiotic-resistant bacteria. By targeting the protein-folding system these pathogens rely on to build their resistance enzymes, we may be able to develop a new class of therapies that work alongside standard antibiotics, restoring their effectiveness and helping clinicians treat infections that are currently very difficult to manage."

Despoina Mavridou, assistant professor of molecular biosciences at UT and study co-author