Antibiotic resistant bacterial infections have become a major problem worldwide. Among Gram positive pathogens, invasive methicillin-resistant Staphylococcus aureus infections (MRSA) and vancomycinresistant enterococcal (VRE) infections represent particular threats. This proposal is a subproject in a Harvard-wide program to address the need to develop new approaches to overcome these infections. The four aims in this subproject are directed towards exploring new compounds, targets, and strategies to overcome MRSA and VRE.
The first aim i s to develop combined chemical and enzymatic methods to make novel phosphoglycolipid antibiotics that inhibit peptidoglycan (PG) biosynthesis by targeting the enzymes that make the glycan chains of PG.
The second aim i s to elucidate the pathway for wall teichoic acid (WTA) biosynthesis in Enterococcus faecalis and assess its potential as an antibacterial target in order to lay the groundwork for inhibitor screening.
The third aim i s to discover novel TarO inhibitors that can be used in combination with beta lactams to overcome MRSA infections.
The fourth aim, to be carried out in collaboration with other subprojects, is to evaluate the compounds we discover in prioritized animal models. These studies will include evaluation of a 8. aureus-selective WTA-active antibiotic that we previously discovered and have already optimized for in vitro activity. The proposed research may lead to the development of new antibiotics for clinical use to treat MRSA and VRE infections.

Public Health Relevance

Antibiotic resistant bacterial infections have become a major problem worldwide. Among Gram positive pathogens, invasive methicillin-resistant Staphylococcus aureus infections (MRSA) and vancomycin-resistant enterococcal (VRE) infections represent particular threats. The proposed work addresses the need to develop new approaches to overcome these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI083214-04
Application #
8202904
Study Section
Special Emphasis Panel (ZAI1-LG-M (M1))
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$414,120
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Truong-Bolduc, Q C; Wang, Y; Chen, C et al. (2017) Transcriptional Regulator TetR21 Controls the Expression of the Staphylococcus aureus LmrS Efflux Pump. Antimicrob Agents Chemother 61:
Gwisai, Tinotenda; Hollingsworth, Nisha Rosita; Cowles, Sarah et al. (2017) Repurposing niclosamide as a versatile antimicrobial surface coating against device-associated, hospital-acquired bacterial infections. Biomed Mater 12:045010
Truong-Bolduc, Q C; Khan, N S; Vyas, J M et al. (2017) Tet38 Efflux Pump Affects Staphylococcus aureus Internalization by Epithelial Cells through Interaction with CD36 and Contributes to Bacterial Escape from Acidic and Nonacidic Phagolysosomes. Infect Immun 85:
Ibberson, Carolyn B; Stacy, Apollo; Fleming, Derek et al. (2017) Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. Nat Microbiol 2:17079
Zheng, Zhaojun; Tharmalingam, Nagendran; Liu, Qingzhong et al. (2017) Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa. Antimicrob Agents Chemother 61:
Saavedra, José T; Schwartzman, Julia A; Gilmore, Michael S (2017) Mapping Transposon Insertions in Bacterial Genomes by Arbitrarily Primed PCR. Curr Protoc Mol Biol 118:15.15.1-15.15.15
Rajagopal, Mithila; Walker, Suzanne (2017) Envelope Structures of Gram-Positive Bacteria. Curr Top Microbiol Immunol 404:1-44
Matano, Leigh M; Morris, Heidi G; Hesser, Anthony R et al. (2017) Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. J Am Chem Soc 139:10597-10600
Lebreton, François; Manson, Abigail L; Saavedra, Jose T et al. (2017) Tracing the Enterococci from Paleozoic Origins to the Hospital. Cell 169:849-861.e13
Nakaminami, Hidemasa; Chen, Chunhui; Truong-Bolduc, Que Chi et al. (2017) Efflux Transporter of Siderophore Staphyloferrin A in Staphylococcus aureus Contributes to Bacterial Fitness in Abscesses and Epithelial Cells. Infect Immun 85:

Showing the most recent 10 out of 116 publications