Bacterial signal transduction and its role in important physiological and developmental processes

The Szurmant laboratory has a long-standing interest in bacterial signal transduction. The focus is on the so-called two-component system, a mechanism that is widely utilized by bacteria in many developmental decisions, such as sporulation, genetic competence development, chemotaxis. From a medical perspective, those systems that contribute to antimicrobial resistance, virulence factor expression and those essential for viability are of particular interest.  The laboratory has a special focus on the study of WalRK, the only essential two-component signal transduction system of bacteria in the phylum Firmicutes. This phylum includes significant human pathogens such as Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecalis and bioterrorism thread Bacillus anthracis. Using molecular genetics techniques, we have identified the role this system plays in bacterial physiology. Some efforts in the lab are directed to WalRK’s involvement in antimicrobial resistance of clinical isolates and testing its utility as an antimicrobial drug target.

Molecular evolution and protein-protein interactions

Proteins in all organisms undergo concerted interactions in order to execute catalytic, structural, transport and many other essential functions. Numerous genetic diseases are caused by mutations that interfere with wild type protein-protein interactions (PPI). Knowledge on all viral-host cell PPIs, such as those important for COVID-19 infection and disease, would greatly speed up new drug discovery. In bacteria, knowledge on all essential PPIs would greatly enhance the complement of antimicrobial drug targets, in the light of multi-drug resistant bacteria.  We developed a widely applicable technology termed Direct Coupling Analysis (DCA), which in combination with experimental techniques has found wide application in the identification of PPI partners and in solving structures of proteins, protein complexes and alternative conformations of signaling proteins. Direct Coupling Analysis relies on the exponentially growing protein sequence databases to mathematically extract contact residue information within and between proteins. We are currently moving this technology forward by trying to understand the amino acid sequence code that dictates not only the structure of PPIs, but also their strength. To this end, we are experimentally sampling directed mutant libraries of thousands of variants of essential interacting protein pairs. In vivo evolution of libraries will inform about the epistatic coupling of amino acid residues on the contact surface between these proteins. Paired with DCA-based computational efforts this approach will provide a leap in our understanding of the protein-sequence code that dictates the strength of an interaction to one day predict all elements of protein function, relying solely on protein sequence.  These efforts hold the long-term promise to help identify genetic determinants of complex diseases based on rare variants. In the context of antibiotic resistance, it can be helpful for predicting patterns of adaptive mutations of pathogens (bacteria and viruses) and contribute to the discovery of new therapeutic strategies.