This Harvard-wide Program on Antibiotic Resistance (HPAR) proposal outlines the design and function of a novel, interdisciplinary, collaborative partnership to develop and test new validated lead compounds for changing the paradigms for treatment of multidrug resistant MRSA, VRE and now VRSA infections. Although discovery and delivery of novel and promising new compounds to the development pipeline is a major overall goal, because this is an academic effort, adding to the base of scientific knowledge that underpins the development of inhibitors for these pathogens;the understanding of resistance, and development of novel new tools for studying host-pathogen interactions and multidrug resistant pathogens are also major goals. This project is being proposed by an accomplished group of scientists with extensive experience in the biochemistry of cell wall biosynthesis and use of that information to design screens and new inhibitors;the molecular biology of model host systems and the use of those systems in novel ways for screening compounds that block the ability of bacteria to harm the host;the biology and molecular genetics of biofilm formation in model systems and the use of that information to identify biofilm disrupting agents;the pathogenesis, genetics and antibiotic resistance of enterococci;and the pathogenesis, molecular biology and clinical treatment of infection caused by multidrug resistant staphylococci. This scientific expertise is complemented by administrative experience that includes service as university Vice President for Research, and President and CEO of a research institute. The goal of the HPAR Administrative Core is to create a cohesive and well functioning whole that is greater than the sum of the individual projects.
The Specific Aims of the Administrative Core are to 1) Provide program management and oversight, 2) Facilitate interactions between participants from the various components of Harvard University, 3) Provide critical infrastructure for fiscal management of the program;4) Provide connectivity to and leverage from other Harvard-wide initiatives;and 5) Provide a single point of contact and active coordination for on-going communication with NIAID and the Program Officer, and other NIAID initiatives.

Public Health Relevance

MRSA infections are common, often invasive and life threating. VRE are leading causes of hospital acquired infection. VRE now have donated vancomycin resistance to MRSA, creating VRSA refractor to this last line antibiotic. The administrative core will assure the smooth operation of this PPG, and will insure that the products generated are much greater than the sum of its parts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083214-07
Application #
8716648
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02114
Rajagopal, Mithila; Martin, Melissa J; Santiago, Marina et al. (2016) Multidrug Intrinsic Resistance Factors in Staphylococcus aureus Identified by Profiling Fitness within High-Diversity Transposon Libraries. MBio 7:
Cheesman, Hilary K; Feinbaum, Rhonda L; Thekkiniath, Jose et al. (2016) Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans. G3 (Bethesda) 6:541-9
Matano, Leigh M; Morris, Heidi G; Wood, B McKay et al. (2016) Accelerating the discovery of antibacterial compounds using pathway-directed whole cell screening. Bioorg Med Chem 24:6307-6314
Selleck, Elizabeth M; Gilmore, Michael S (2016) Oxygen as a Virulence Determinant in Polymicrobial Infections. MBio 7:
Gaca, Anthony O; Gilmore, Michael S (2016) Killing of VRE Enterococcus faecalis by commensal strains: Evidence for evolution and accumulation of mobile elements in the absence of competition. Gut Microbes 7:90-6
Pasquina, Lincoln; Santa Maria Jr, John P; McKay Wood, B et al. (2016) A synthetic lethal approach for compound and target identification in Staphylococcus aureus. Nat Chem Biol 12:40-5
Kim, Wooseong; Fricke, Nico; Conery, Annie L et al. (2016) NH125 kills methicillin-resistant Staphylococcus aureus persisters by lipid bilayer disruption. Future Med Chem 8:257-69
Rajagopal, Mithila; Walker, Suzanne (2016) Envelope Structures of Gram-Positive Bacteria. Curr Top Microbiol Immunol :
Newman, Martin; Ausubel, Frederick M (2016) Introduction to Gene Editing and Manipulation Using CRISPR/Cas9 Technology. Curr Protoc Mol Biol 115:31.4.1-6
Van Tyne, Daria; Ciolino, Joseph B; Wang, Jay et al. (2016) Novel Phagocytosis-Resistant Extended-Spectrum β-Lactamase-Producing Escherichia coli From Keratitis. JAMA Ophthalmol 134:1306-1309

Showing the most recent 10 out of 97 publications