The Infectious Diseases Society of America recently identified a list of antibiotic-resistant pathogens that can escape the effect of most antimicrobial agents. These problematic pathogens include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., which are collectively abbreviated as ESKAPE. Therefore, there is an urgent need to develop effective antibiotics to keep up with antibiotic resistance. Paenipeptins are novel synthetic linear lipopeptides, which are made of 9 amino acid residues and a fatty acyl group at the N-terminus. They showed highly potent activity in combination with clarithromycin against Gram- negative pathogens in vitro. The overall goal of this project is to develop novel linear lipopeptide antibiotic potentiators, which can be co-administered with FDA-approved antibiotics, to expand their antimicrobial spectrum and enhance the antibiotic activity for the treatment of infections associated with polymyxin-resistant and carbapenem-resistant pathogens. To achieve this goal, the following two aims are set.
Aim 1 : Evaluate the synergistic effect between paenipeptin analogues and clarithromycin in vitro against a large number of carbapenem-resistant clinical isolates and investigate the mechanism of synergism.
Aim 2 : Develop antimicrobial-loaded hydrogels for localized delivery of paenipeptin-clarithromycin mixture for topical treatment of wound infections.

Public Health Relevance

The urgent need for new and effective antimicrobial agents has been emphasized in a recently-announced US initiative, the National Strategy for Combating Antibiotic Resistant Bacteria. The overall goal of this proposal is to develop novel linear lipopeptide potentiators as antibiotic adjuvants to treat bacterial infections caused by drug-resistant Gram-negative pathogens, including polymyxin-resistant and carbapenem-resistant pathogens. Success of this study could speed the development of new antibiotic drugs for treatment of hard-to-cure infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI146693-01
Application #
9808875
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xu, Zuoyu
Project Start
2019-07-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205