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Targeting the host response to limit infection by intracellular bacterial pathogens

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI141302-01
Agency Tracking Number: R41AI141302
Amount: $148,836.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA17-303
Timeline
Solicitation Year: 2017
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-07-01
Award End Date (Contract End Date): 2019-06-30
Small Business Information
379 REAS FORD RD, STE 1
Earlysville, VA 22936-2407
United States
DUNS: 080783909
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 MARC SEAMAN
 (770) 861-0945
 marc.seaman@blueridgebiosciences.com
Business Contact
 MARC HROVATIC
Phone: (540) 239-0668
Email: marc.hrovatic@axonconnected.com
Research Institution
 VANDERBILT UNIVERSITY MEDICAL CENTER
 
1161 21ST AVE S, STE D3300 MCN
NASHVILLE, TN 37232-0011
United States

 Domestic Nonprofit Research Organization
Abstract

Antibiotic development has traditionally focused on drugs that target the pathogen but resistance inevitably
developsAn attractive alternative is to develop drugs that target the host response and in particular for
facultative obligate intracellular bacterial pathogenswhich rely on the host for disease progressionIntracellular bacterial pathogens manipulate the host cytoskeletal system to their advantage during various
stages in infectionIn particular a number of medically important pathogens activate the MEK ERK cascadewhich is known to be important in cytoskeletal dynamicsFDA approved inhibitors of MEK are available but
their efficacy is limited by their toxicityWe discovered and developed a specific small molecule inhibitor for
RSKa downstream effector of the MEK ERK signaling pathwayIn preliminary experimentsusing
Yersinia pseudotuberculosis as a model intracellular bacterial systemwe identified that RSKinhibition
reduced the number of viable bacteria in infected macrophageswhich correlated with inhibition of Ypseudotuberculosis induced cytoskeletal rearrangementFurthermorebacterial infection can result in sepsiswhich results in a loss of epithelial integrityImportantlywe identified that RSKregulates a gene signature
enriched in immune response signaling in epithelial cellssuggesting that a RSKinhibitor will dampen the
epithelial generated immune response and therebyprotect epithelial integrityIn support of these data
inhibiting MEK signaling pathway was found to decrease organ dysfunctionFor the phase I programBlue
Ridge BiosciencesLLCa reagent discovery and development companyin collaboration with Vanderbilt
University Medical Centerwill assess the feasibility of targeting RSKas a drug target for facultative obligate
intracellular bacterial pathogens that activate the MEK ERK pathwayFrancisella tularenis will be used as
proof of principleThe Specific Aims aredetermine whether RSKlimits propagation of Ftularenis in
primary macrophages in vitrodetermine whether inhibition of RSKprotects the integrity and viability of
lung epithelial cells in vitroandtest whether inhibition of RSKusing a RSKknockout mouse model
will ameliorate infection by Ftularenis in vivoData generated in this proposal will be analyzed using the
appropriate statistics for end point and longitudinal analysisThese data will be used to support a phase II for
the continued development of a RSKinhibitor as a novel strategy for combating infection NarrativeAntibiotic resistance is a major global health problemThis proposal will provide preliminary data to
support the development of a novel therapeutic strategy that targets the host response to infection by
intracellular bacterial pathogensTargeting the host response to infection will dramatically reduce the
incidence of resistance

* Information listed above is at the time of submission. *

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