The longterm goals of the project are to identify the full array of efflux pumps of Staphylococcus aureus that contribute to multiple antimicrobial resistance and to elucidate the determinants of their expression, their role in microbial physiology and their effect on bacterial response to antimicrobials in infection. The work will focus on genetic analysis of regulatory elements and on bacterial fitness and response to antimicrobials in a subcutaneous abscess model, collaborating with other project groups to assess the efficacy of novel antimicrobial compounds in abscesses and the extent to which efflux pumps affect that efficacy. There are four specific aims: 1) assess the effects of NorB, NorD, and Tet38 efflux pumps and their regulators on response to antimicrobials in animal models of infection;2) evaluate the regulation of expression of abcA encoding an ABC family efflux pump and assess its effects on membrane and cell wall-targeting agents;3) analyze the global array of pumps over expressed in an abscess environment and determine their contribution to resistance to established agents and novel compounds;and 4) test novel compounds discovered in other subprojects of the program project for resistance to efflux pump expression and for efficacy and development of resistance in mammalian infection models. The work will utilize genetic manipulation and allelic exchange in S. aureus, measurements of gene expression with RT-PCR, and established murine models of infection (subcutaneous abscess, renal abscess, lethality) utilizing a genomically defined strains of methicillin resistant and other S. aureus. The overall goal of the program project is to take a well-integrated, multidisciplinary approach to understanding antibiotic resistance development and transmission, and to integrate that effort with the search for compounds that compromise resistant pathogens, including methicillin-resistant S. aureus (MRSA), by inhibiting novel targets and pathways. This project will add to understanding of resistance mechanisms related to multidrug efflux pumps and provide strains for testing the effect of such pumps on novel compounds active against new targets and pathways. It will also utilize mammalian models of a common MRSA infection to test compound activity in vivo.

Public Health Relevance

Multidrug resistance in S. aureus is an increasing clinical and public health problem that requires additional understanding of its mechanisms of development and spread and establishment of novel targets that may be exploited to develop new effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083214-05
Application #
8376876
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
$402,108
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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