Drug resistance of pathogenic microbes in healthcare and community settings is a quickly growing and extremely dangerous health threat. There is consequently a critical need for the development of alternative therapeutics to tackle drug resistance. The objective of this R01 application is to investigate a novel non-antibiotic approach, antimicrobial blue light (aBL), to target/treat microbes including drug-resistant strains In this application, we propose five specific aims.
In Aim 1, we will determine the susceptibility f a wide range of important microbes to aBL at 405, 415 or 470 nm wavelength. Both planktonic cultures and biofilms will be studied.
In Aim 2, we will determine whether microbes can develop resistance to aBL; and elucidate the molecular mechanism of mutant development if aBL resistance develops.
In Aim 3, we will investigate the potential side effects of aBL on relevant host cells.
In Aim 4, we will elucidate the mechanism of action of aBL. The study will be carried out in vitro by looking for a correlation between the level of endogenous photosensitizers in microbial cells and corresponding aBL susceptibility of microbes. Isogenic strains of representative microbes that differ only in the level of endogenous photosensitizers will be used.
In Aim 5, we will demonstrate the effectiveness of aBL for prophylaxis and treatment of representative infections (urinary tract infections, surgical site infections, etc.) in murine modes. Both monomicrobial and polymicrobial infections will be studied. aBL will be initiated at 30 min, 4 h or 48 h after microbial inoculation. Bioluminescence imaging will be performed to noninvasively monitor in real time the extent of infection in living animals. The efficacy found with aBL will be compared with that of clinically used antibiotics. Successful completion of these specific aims will provide the foundation required to assess the effectiveness (Aims 1 and 5), potential side effects (Aims 2 and 4), and mechanism of action (Aim 3) of aBL inactivation of microbes, and will help establish protocols for the use of this therapeutic approach.

Public Health Relevance

There is a critical need for the development of alternative therapeutics to tackle drug resistance of pathogenic microbes. This application is to explore the use of a novel non-pharmacological approach, antimicrobial blue light, for targeting/treating microbes that are of significant clinical concern and are resistant to currently approved drugs. If antimicrobial blue light can be shown to be both effective and safe, this research will address the serious problem of emerging drug-resistant microbes by providing a much-needed non-pharmacological approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI123312-01
Application #
9080319
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
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