Molecular mechanisms of cbra transceptor signaling in pseudomonas

The National Institute of Allergy and Infectious Diseases awarded Michigan State University $413,092 on June 8, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the molecular mechanisms of CBRA transceptor signaling in Pseudomonas aeruginosa.

The research examines how the CBRA/B regulatory network controls carbon and nitrogen metabolism, biofilm formation, and virulence in Pseudomonas species. CBRA functions as a unique "transceptor" protein that integrates membrane transport and sensor kinase activities within a single polypeptide, importing histidine and other nutrients while simultaneously signaling through phosphorylation of the response regulator CBRB. The project uses cryo-electron microscopy alongside biochemical and functional assays to elucidate the structural and functional properties governing how CBRA couples histidine transport with intracellular signaling. This work addresses the urgent need for novel therapeutic strategies targeting global regulatory systems as an alternative to conventional antibiotics, particularly against multidrug-resistant Pseudomonas strains that cause healthcare-associated infections resistant to standard treatment.

Performance runs through May 31, 2028, at Michigan State University's East Lansing, Michigan campus.

Abstract

Pseudomonas aeruginosa is a leading cause of healthcare-associated infections, largely due to its ability to form biofilms and rapidly develop resistance to antibiotics. These infections are notoriously difficult to treat, and the emergence of multidrug-resistant (MDR) strains has only heightened concerns. With conventional antibiotics becoming less effective, novel therapeutic strategies are urgently needed to combat persistent pseudomonas infections. One promising approach is targeting global regulatory systems that control multiple interconnected pathogenic processes, including biofilm formation, virulence, and antibiotic resistance. Disrupting these regulatory networks could provide an alternative to traditional antibiotics by impairing adaptation and survival. One such global regulatory system is the cbra/b network, a central regulator of carbon/nitrogen metabolism, biofilm formation, and virulence in pseudomonas species. Cbra is a unique "transceptor" protein, integrating membrane transport and histidine kinase activities within a single polypeptide. Cbra functions both as a transporter, importing histidine and other carbon/nitrogen sources, and as a sensor kinase that phosphorylates the response regulator cbrb to modulate downstream signaling. Cbra/b governs expression of genes essential for nutrient uptake, environmental adaptation, biofilm formation, and overall virulence. Despite the established importance of cbra/b in pseudomonas infections, the molecular mechanisms by which cbra coordinates membrane transport and signaling remain poorly understood. This project aims to unravel these mechanisms by investigating the structural and functional properties of cbra in molecular detail. Using cryo- electron microscopy (cryo-EM) alongside biochemical and functional assays, we will examine how cbra couples histidine transport with intracellular signaling to regulate multiple pathways involved in pseudomonas virulence and metabolism. Specifically, we will explore how structural changes in cbra influence its transport and kinase functions, and how these modifications enable the activation of cbrb in response to environmental signals. By providing high-resolution structural insights into the cbra/b system, this research will enhance our understanding of transceptor-mediated bacterial signaling. The findings will not only reveal fundamental aspects of pseudomonas adaptability and virulence but also inform novel therapeutic strategies targeting the cbra/b network. Ultimately, this work has the potential to drive innovative approaches for disrupting pseudomonas global regulatory systems and tackling MDR p. Aeruginosa infections.