Multidrug resistance (MDR) in pathogenic bacteria poses a serious public-health problem. Previously, we have discovered cefoxitin can render methicillin-resistant S. aureus (MRSA) strains sensitive again to oxacillin. We thus hypothesize that small molecules may augment the bactericidal activity of ?-lactams against Gram+ pathogens. After screening a ~60,000 small- molecule library, we obtained candidate compounds with activity against MRSA with sub-MIC oxacillin. While one of the compound DNAC-2 has broad-spectrum activity and low level of toxicity, its core structure shares similarity to 5-hydroxy-quinoline, known to have anti-bacterial activity. To develop novel derivatives, we synthesized a series of unique analogs one of which is called DNAC-23a. In combination with oxacillin, DNAC-23a led to a 64-fold decrease in oxacillin MIC of MRSA strain USA300, rendering an MRSA to a MSSA phenotype. We propose to further characterize DNAC-23a with the following two specific aims: I) to identify the target of DNAC-23a; II) to conduct Structure-Activity-Relationship studies of DNAC-23a. The goal of these studies is to identify novel derivatives with improved efficacy, improved solubility and minimal toxicity. Future studies will focus on the optimal PK/PD values of these compounds, thus enabling us to identify a ?lead compound? for future drug development. As treatment options for resistant Gram+ pathogens are limited, discovery of novel compounds that extend the usage of current beta-lactams represents a potential advance in drug development.

Public Health Relevance

Multidrug resistance (MDR) in pathogenic bacteria poses a serious public-health problem. We have identified a novel compound called DNAC-23a that led to a 64-fold decrease in oxacillin minimum inhibitory concentration of a methicillin-resistant Staphylococcus aureus strain. We propose to optimize this compound by making a series of analogs which we will characterize.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI130540-01
Application #
9296686
Study Section
Special Emphasis Panel (ZRG1-IDM-P (07)S)
Program Officer
Xu, Zuoyu
Project Start
2017-02-15
Project End
2019-01-31
Budget Start
2017-02-15
Budget End
2018-01-31
Support Year
1
Fiscal Year
2017
Total Cost
$212,350
Indirect Cost
$55,800
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755