Traditionally, platelets have been thought to promote the development of endovascular infections such as infective endocarditis (lE), by providing a adhesive surface upon damaged endothelium for colonization by circulating microorganisms. In contrast, recent evidence suggests that platelets serve an important host defense role against the development of endovascular infections at sites of endothelial damage via local secretion of endogenous microbicidal peptides , termed thrombin-induced platelet microbicidal protein or tPMP. Preliminary studies revealed the following data: i) tPMP kills the most common endovascular pathogens in nM concentrations; ii) microbial strains from bacteremic patients without IE were significantly more susceptible in vitro to the microbicidal action of tPMP than strains from bacteremic patients with IE. This suggested that phenotypic tPMP- resistance provides the organism with a survival advantage as regards induction of IE; iii) tPMP is synergistic in combination with conventional antibiotics in the killing and growth.inhibition of S. aureus ; and iv) the bacterial cell membrane appears to be a primary target for tPMP-induced lethality.The overall purpose of the current proposal is to define the fundamental microbicidal mechanisms of tPMP against S. aureus, the most virulent and commonest overall cause of endovascular infections, by: i) quantifying tPMP binding to the staphylococcal membrane; ii) delineating the role of bacterial transmembrane potential in the staphylocidal actions tPMP; iii) identifying membrane assembly of tPMP and subsequent membrane permeabilization and pore formation by tPMP; and iv) defining the mechanisms of phenotypic tPMP resistance, using genetically-related staphylococcal strains from a common genomic background which differ phenotypically in tPMP susceptibility. These studies may eventually define novel staphylocidal targets or unique staphylocidal mechanisms. These studies will also provide a solid foundation for defining the staphylocidal domains of tPMP by molecular biologic techniques. tPMP will also serve as a design template for development of synthetic congeners with potent antimicrobial activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039108-04
Application #
6124395
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Miller, Marissa A
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2001-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$198,623
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
Yang, Soo-Jin; Mishra, Nagendra N; Kang, Kyoung-Mi et al. (2018) Impact of Multiple Single-Nucleotide Polymorphisms Within mprF on Daptomycin Resistance in Staphylococcus aureus. Microb Drug Resist 24:1075-1081
Abdelhady, Wessam; Bayer, Arnold S; Gonzales, Rachelle et al. (2017) Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains. Antimicrob Agents Chemother 61:
Mishra, Nagendra N; Tran, Truc T; Seepersaud, Ravin et al. (2017) Perturbations of Phosphatidate Cytidylyltransferase (CdsA) Mediate Daptomycin Resistance in Streptococcus mitis/oralis by a Novel Mechanism. Antimicrob Agents Chemother 61:
Kang, Kyoung-Mi; Mishra, Nagendra N; Park, Kun Taek et al. (2017) Phenotypic and genotypic correlates of daptomycin-resistant methicillin-susceptible Staphylococcus aureus clinical isolates. J Microbiol 55:153-159
Xiong, Yan Q; Abdelhady, Wessam; Tang, Chieh 'Genna' et al. (2016) Comparative efficacy of telavancin and daptomycin in experimental endocarditis due to multi-clonotype MRSA strains. J Antimicrob Chemother 71:2890-4
Miller, William R; Bayer, Arnold S; Arias, Cesar A (2016) Mechanism of Action and Resistance to Daptomycin in Staphylococcus aureus and Enterococci. Cold Spring Harb Perspect Med 6:
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
Khatib, Tala O; Stevenson, Heather; Yeaman, Michael R et al. (2016) Binding of Daptomycin to Anionic Lipid Vesicles Is Reduced in the Presence of Lysyl-Phosphatidylglycerol. Antimicrob Agents Chemother 60:5051-3
Bayer, Arnold S; Mishra, Nagendra N; Cheung, Ambrose L et al. (2016) Dysregulation of mprF and dltABCD expression among daptomycin-non-susceptible MRSA clinical isolates. J Antimicrob Chemother 71:2100-4
Li, Liang; Cheung, Ambrose; Bayer, Arnold S et al. (2016) The Global Regulon sarA Regulates ?-Lactam Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus In Vitro and in Endovascular Infections. J Infect Dis 214:1421-1429

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