Friday, April 19, 2024
4/19/2024
Project Summary Adhesion of bacteria to host cells is an essential step in the initiation of an infection, and yet, the mechanisms that make bacteria sticky are not fully understood. A long list of human pathogens, including Pseudomonas aeruginosa in the lungs of cystic fibrosis patients, become anchored to host cells using thin (<10 nm), long (>1 µm), and mechanically strong (capable of withstanding pN to nN forces) filaments called pili. The pili latch onto surfaces through receptor-ligand interactions, and only very recently discovered, extracellular electron transfer. Bacteria with more electrically conductive pili tend to be more adhesive. By elucidating the mechanistic basis for this observation, we seek to establish design rules for manipulating microbe-host interactions for therapeutic purposes. New therapies that inhibit pili-mediated charge transfer could be realized to block the formation of biofilms by pathogenic species, or to correct imbalances in the populations of adhered intestinal tract microbiota. To realize these possibilities, we specifically aim to establish the relative contributions of mechanical and electrical mechanisms in bacterial adhesion mediated by pili. Alchemical and steered molecular dynamics simulations will be used to assess the change in stability and tensile strength of pili as a function of point mutations associated with differently adherent bacteria. A quantum mechanical/molecular mechanical implementation of Marcus theory, combined with a kinetic model, will be used to compute the electrical conductivity of different pili. The pili will feature mutations according to a direct electronic modulation strategy: Standard residues will be replaced with substituent-bearing unnatural counterparts that have similar steric but different electronic properties. The obtained structure-function insights will drive the second aim of our research to rationally design and evaluate pili antagonists. Fragment dissolved molecular dynamics will be used to identify prospective binding sites, into which ligands will be docked in a high throughput screen and optimized by free energy perturbation techniques. The work will be undertaken at Yale University under the mentorship of Professor Nikhil S. Malvankar of the Microbial Science Institute within the Molecular Biophysics and Biochemistry department, and in collaboration with John Randolph Huffman Professor Victor S. Batista of the Chemistry department. Their combined expertise with bacterial nanowires (Dr. Malvankar) and the theoretical modeling of interfacial electron transfer processes (Dr. Batista) will serve as unique assists for the success of the project. The fellowship training plan involves publishing in high impact journals and presenting at conferences for the biomedical and chemistry communities. It also includes the opportunity to mentor graduate students. The career development plan includes attending professional development workshops organized by the Office of Postdoctoral Affairs, as well as courses relevant to the project.
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