. While rates of antibiotic resistance bacterial infections continue to rise, our development of new antimicrobial agents has stagnated. The high failure rate of new candidate compounds demands the development of alternative pipelines for the discovery of new antimicrobial agents to prevent our slide back to the pre-antibiotic medical era. Our objective in this proposal is to develop and implement a new molecular approach to drug screening for an in-depth study of peptide chemistry with antimicrobial activity against antibiotic-resistant, Gram-negative bacterial pathogens. Our platform creates microenvironments for individual bacteria and peptide sequences to interact under physiologically relevant conditions, within a mixed bacterial population. Lytic events are measured using next-generation sequencing, allowing rapid and batch screening of millions of peptides in one tube. This proposal offers a quantum leap forward in antimicrobial peptide research. Completion of the planned work is expected to have a positive translational impact by greatly expanding our understanding of peptide chemistry with antimicrobial activity and identify new bacterial targets for therapeutic targeting, both of which will likely support the development of new antimicrobials and approaches to fight antibiotic-resistant bacteria.

Public Health Relevance

. 700,000 people die annually from antibiotic-resistant bacterial infections. This number is projected to increase more than 10-fold over the next three decades, unless new treat options are found. Our objective in this proposal is to develop and implement a new molecular approach to drug screening for an in-depth study of peptide chemistry with antimicrobial activity against antibiotic-resistant, Gram-negative bacterial pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI125337-03
Application #
9474573
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2016-05-15
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
Tucker, Ashley T; Leonard, Sean P; DuBois, Cory D et al. (2018) Discovery of Next-Generation Antimicrobials through Bacterial Self-Screening of Surface-Displayed Peptide Libraries. Cell 172:618-628.e13
Knauf, Gregory A; Cunningham, Ashley L; Kazi, Misha I et al. (2018) Exploring the Antimicrobial Action of Quaternary Amines against Acinetobacter baumannii. MBio 9:
Reuther, James F; Goodrich, Andrew C; Escamilla, P Rogelio et al. (2018) A Versatile Approach to Noncanonical, Dynamic Covalent Single- and Multi-Loop Peptide Macrocycles for Enhancing Antimicrobial Activity. J Am Chem Soc 140:3768-3774