Multidrug resistant Staphylococcus aureus (e.g., methicillin resistant [MRSA]) and enterococci (e.g., vancomycin resistant [VRE]) emerged in the 1960's and 1980's, and are leading causes of life-threatening infection in the hospital - more recently also in the community. Critically, after 20 years of containment, vancomycin resistance moved from VRE to MRSA, creating VRSA, and there are now 10 well documented cases. The overall goal of this program project is to identify and develop new drugs for treating infections caused by VRSA and VRE. This will be conducted hand-in-hand with studies to understand the development and proliferation of resistance in the multidrug resistant microbes being targeted in this Subproject. Overarching Goals: Determine what genetic or biological events led to the breach of containment of vancomycin resistance in VRE and transfer to VRSA, and demonstrate the activity of new compounds against them, by discovering and examining: -a known genetic event (insertional inactivation of a plasmid borne postsegregational killing TA module), - unknown traits within the genomes of the 10 well documented VRSA strains, and the putative VRE donors coisolated with them, - genetic and metabolic compatibilities, that may have predisposed them to coexist in mixed infection or participate in vancomycin resistance transfer, and - the efficacy of compounds developed in this PPG against these highly multidrug resistant, hospital adapted strains By understanding the basis for transfer as well as the nature of these increasingly resistant strains, we will be better positioned to assess the threat of continued erosion of antibiotic sensitivity in leading causes of hospital and community infection in the US, and will be alert to the types of conditions that promote this transfer.

Public Health Relevance

MRSA infections are common, often invasive and life threatening. VRE are leading causes of hospital acquired infection. VRE now have donated vancomycin resistance to MRSA, creating VRSA refractor to this last line antibiotic. This research aims to understand these multidrug resistant strains and the resistance transmission, and assess the efficacy of novel compounds against them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083214-05
Application #
8376874
Study Section
Special Emphasis Panel (ZAI1-LG-M)
Project Start
2012-09-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$291,462
Indirect Cost
$36,727
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:

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