Antimicrobial peptides from platelets (termed platelet microbicidal proteins [PMPs]) play a critical role in the innate immune system especially in the context of host defenses against endovascular infections. During endovascular colonization, the invading organism must contend with this limb of the innate immune system to persist and proliferate at such sites of infection. The mechanisms by which the organism can circumvent the effects of PMPs to survive within the endovascular space are not well understood. This is especially true of "adaptive responses" that enable PMP-susceptible organisms to survive exposures to these peptides. This proposal will employ three integrated specific aims to address our overall hypothesis: the cell membranes of endovascular pathogens such as Staphylococcus aureus are able to respond to and survive PMP exposures by a coordinated series of lipid biosynthetic adaptations, termed "homeoviscous adaptations". The three specific aims will be: 1) to fully characterize the homeoviscous cell membrane responses in vitro;2) to model these homeoviscous changes within customized liposomes ex vivo;and 3) to determine whether homeoviscous adaptations occur within relevant biomatrices and endovascular lesions in vivo.
Aim 1 will utilize a series of in vitro techniques to examine the homeoviscous responses, including membrane fatty acid and phospholipid profiling, phospholipid assymetry and membrane fluidity. In addition, we will pair these analyses with a temporal assessment of expression by a series of prioritized membrane lipid biosynthetic genes.
In Aim 2, we will employ large unilamellar vesicles whose membrane lipid contents will mirror those that emerge in vitro from Aim 1. These studies will define and quantify the impacts of homeoviscous adaptations on PMP:membrane interactions.
Aim 3 will use the ex vivo biomatrix model and the rabbit model of endocarditis to explore the in vivo relevance of homeoviscous adaptations. The merging of in vitro-ex vivo-in vivo aspects of an important biologic event may well enable design of innovative strategies to prevent the organism from evolving these adaptations. This translational approach is within the mission of the NIH for their broad research roadmap. Lay Summary. The research in this proposal seeks to understand how bacteria can withstand the exposures to an important part of the host defense system (natural peptide antibiotics). This may enable design of new of strategies to kill such bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039108-14
Application #
8022935
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Huntley, Clayton C
Project Start
1996-12-01
Project End
2012-05-31
Budget Start
2011-03-01
Budget End
2012-05-31
Support Year
14
Fiscal Year
2011
Total Cost
$320,705
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Li, Liang; Cheung, Ambrose; Bayer, Arnold S et al. (2016) The Global Regulon sarA Regulates β-Lactam Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus In Vitro and in Endovascular Infections. J Infect Dis 214:1421-1429
Chaili, Siyang; Cheung, Ambrose L; Bayer, Arnold S et al. (2016) The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action. Infect Immun 84:459-66
Bayer, Arnold S; Mishra, Nagendra N; Chen, Liang et al. (2015) Frequency and Distribution of Single-Nucleotide Polymorphisms within mprF in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides. Antimicrob Agents Chemother 59:4930-7
Reyes, Jinnethe; Panesso, Diana; Tran, Truc T et al. (2015) A liaR deletion restores susceptibility to daptomycin and antimicrobial peptides in multidrug-resistant Enterococcus faecalis. J Infect Dis 211:1317-25
Karchmer, Adolf W; Bayer, Arnold S (2015) Editorial commentary: surgical therapy for Staphylococcus aureus prosthetic valve endocarditis: proceed with caution (Caveat Emptor). Clin Infect Dis 60:750-2
Gaupp, Rosmarie; Lei, Shulei; Reed, Joseph M et al. (2015) Staphylococcus aureus metabolic adaptations during the transition from a daptomycin susceptibility phenotype to a daptomycin nonsusceptibility phenotype. Antimicrob Agents Chemother 59:4226-38
Munita, Jose M; Bayer, Arnold S; Arias, Cesar A (2015) Evolving resistance among Gram-positive pathogens. Clin Infect Dis 61 Suppl 2:S48-57
Xiong, Yan Q; Sharma-Kuinkel, Batu K; Casillas-Ituarte, Nadia N et al. (2015) Endovascular infections caused by methicillin-resistant Staphylococcus aureus are linked to clonal complex-specific alterations in binding and invasion domains of fibronectin-binding protein A as well as the occurrence of fnbB. Infect Immun 83:4772-80
Abdelhady, Wessam; Chen, Liang; Bayer, Arnold S et al. (2015) Early agr activation correlates with vancomycin treatment failure in multi-clonotype MRSA endovascular infections. J Antimicrob Chemother 70:1443-52
Lauridsen, Trine K; Park, Lawrence; Tong, Steven Y C et al. (2015) Echocardiographic Findings Predict In-Hospital and 1-Year Mortality in Left-Sided Native Valve Staphylococcus aureus Endocarditis: Analysis From the International Collaboration on Endocarditis-Prospective Echo Cohort Study. Circ Cardiovasc Imaging 8:e003397

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