This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the 1980's we demonstrated that antibiotics that inhibit bacterial protein synthesis have greater efficacy than cell wall active agents in the treatment of severe group A streptococcal and clostridial myonecrosis. Toxin suppression has become a critically important goal in the treatment of aggressive infections due to group A streptococcus, histotoxic clostridial species and Staphylococcus aureus. The impact of antibiotic-induced toxin upregulation has not been examined in the context of other life-threatening, toxin-mediated infections such as clostridial gas gangrene, streptococcal toxic shock syndrome or Clostridium difficile-associated diarrhea (CDAD). We hypothesize that upregulation of toxic gene expression by Beta-lactam antibiotics occurs in several clinically impotant Gram positive pathogens and is mediated by a common Cell Signaling pathway following engagement of penicillin-binding proteins.
In Specific Aim 1 we will elucidate the roles of agr, RNAIII and other toxin regulatory pathways in nafcillin-induced upregulation of exotoxin production in S. aureus.
In Specific Aim 2 we will compare the effects of antibiotics associated with triggering CDAD (clindamycin, ampicillin and ciprofloxacin) and those currently used for C. difficile treatment (vancomycin and metronidazole) on production of Toxins A and B by C. difficile.
In Specific Aim 3 we will compare the growth phase-dependent transcriptome of group A streptococcus in the presence and absence of subinhibitory concentrations of beta-lactam antibiotics.
In specific Aim 4 we will investigate innate immune system recognition of and response to beta-lactam-treated S aureus, group A streptococcus, C perfringens and C. difficile. Understanding the mechanisms responsible for, and the immune consequences of, antibiotic-induced toxin upregulation in these organisms will enable a more rational approach to antibiotic therapy.
|Simmons, Aaron B; Merrill, Morgan M; Reed, Justin C et al. (2016) Defective Angiogenesis and Intraretinal Bleeding in Mouse Models With Disrupted Inner Retinal Lamination. Invest Ophthalmol Vis Sci 57:1563-77|
|Altieri, Nicholas; Hudock, Daniel (2016) Normative data on audiovisual speech integration using sentence recognition and capacity measures. Int J Audiol 55:206-14|
|Uribe-Convers, Simon; Settles, Matthew L; Tank, David C (2016) A Phylogenomic Approach Based on PCR Target Enrichment and High Throughput Sequencing: Resolving the Diversity within the South American Species of Bartsia L. (Orobanchaceae). PLoS One 11:e0148203|
|Zavala, Anamaria G; O'Dowd, John M; Fortunato, Elizabeth A (2016) Infection of a Single Cell Line with Distinct Strains of Human Cytomegalovirus Can Result in Large Variations in Virion Production and Facilitate Efficient Screening of Virus Protein Function. J Virol 90:2523-35|
|Bowman, Kole; Rose, Jack (2016) Estradiol stimulates glycogen synthesis whereas progesterone promotes glycogen catabolism in the uterus of the American mink (Neovison vison). Anim Sci J :|
|Jones, Jesse A; Price, Emily; Miller, Donovan et al. (2016) A simplified protocol for high-yield expression and purification of bacterial topoisomerase I. Protein Expr Purif 124:32-40|
|Rasmussen, Erin B; Robertson, Stephen H; Rodriguez, Luis R (2016) The utility of behavioral economics in expanding the free-feed model of obesity. Behav Processes 127:25-34|
|Mahoney, Colin T; Lawyer, Steven R (2016) Delay and probability discounting among payday and title loan recipients. Behav Processes 125:13-8|
|Yano, Hirokazu; Wegrzyn, Katarznya; Loftie-Eaton, Wesley et al. (2016) Evolved plasmid-host interactions reduce plasmid interference cost. Mol Microbiol 101:743-56|
|Li, Xiaobin; Wang, Yafei; Brown, Celeste J et al. (2016) Diversification of broad host range plasmids correlates with the presence of antibiotic resistance genes. FEMS Microbiol Ecol 92:|
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