Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Is inhibiting pili electrical conductivity a new anti-virulence strategy?

Award Number: F32GM142247
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2022

Group Awards By:

View Award Description

Is inhibiting pili electrical conductivity a new anti-virulence strategy? - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$284 )
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	10/31/2023	NEW	-$284
														Subtotal = -$284

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	12/24/2021	NEW	$66,390
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	1	12/24/2021	NEW	$0
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	002	1	5/25/2022	NEW	$1,192
														Subtotal = $67,582

Grand Total All Awards = $67,298

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Is inhibiting pili electrical conductivity a new anti-virulence strategy?

Award Number: F32GM142247

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer