Tuesday, October 23, 2018
Kayla D. McConnell
Department of Chemistry
Mississippi State University
Streptococcus pneumoniae (pneumococcus) can be naturally found in the respiratory tract of asymptomatic individuals. However, in populations with compromised immune systems; such as that of the young, the elderly and persons with diseases that suppress the immune system, pneumococcus can become invasive and life-threatening. The 10 most predominant S. pneumoniae serotypes account for approximately 62% of invasive bacterial disease worldwide, carrying a fatality rate of 8% for children and 22% for adults. In the United States the detection and treatment of streptococcus infection incurred $3.5 billion in medical costs. Antibiotic treatment for those not vaccinated is available, however numerous drug-resistant strains of pneumococcus have been identified, and in 30% of severe S. pneumoniae infections, complete resistance to one or more antibiotics is present. Recent research has been directed toward new avenues for treatment of disease via disrupting biomolecular interactions, specifically metal-dependent transcription factor activity.
Streptococcus zinc-efflux activator (SczA), is a zinc-dependent transcription factor found within Streptococcus strains with the primary responsibility of metal-exportation via the regulation of the cation diffuser facilitator (czcD). In this presentation, I will discuss the proposed mechanism by which SczA accomplishes zinc cellular-efflux as a way to maintain cell homeostasis and prevent rapid apoptosis in streptococci strains. Site directed protein mutagenesis, as well as metal-ion binding studies, including investigating Mn/Zn bioavailability ratio influences, will be discussed. Studies have shown that binding of two zinc ions per protomer and binding at both sites is required for operator sequence recognition and activation of czcD over-expression. Also discussed will be S. pneumoniae overall resistance to zinc toxicity and survival rates in infected human macrophages.
Characterization of Streptococcus Zinc-Efflux Activator (SczA): A novel transcription factor responsible for metal-ion homeostasis
Kayla D. McConnell
1. Centers for Disease Control and Prevention, Active Bacterial Core Surveillance (ABCs) Report , Emerging Infections Program Network, Streptococcus pneumoniae. https://www.cdc.gov/abcs/reports-findings/surv-reports.html (accessed 2018).
Yearly report available to the public concerning the surveillance of bacterial infection prevalence in the United States and in some cases, abroad.
2. Centers for Disease Control and Prevention, Antibiotic Resistance Threats in the United States. https://www.cdc.gov/drugresistance/threat-report-2013/index.html (accessed 2018).
Report compiled by the CDC outlining current antibiotic resistance threats and ways in which individuals, as well as healthcare facilities and providers can help stop the spread of these threats.
3. Centers for Disease Control and Prevention, Pneumococcal Vaccination. https://www.vaccines.gov/diseases/pneumonia/index.html (accessed 2018).
Discusses the available vaccinations for pneumococcus, including who is vaccinated, and at what age.
4. Feldman, C.; Anderson, R., Epidemiology, virulence factors and management of the pneumococcus. Faculty of 1000 Research 2016, 5, 1-11.
Review article that discusses the worldwide mortality of pneumococcal infections, including the prevalence of community acquired pneumonia and healthcare cost associated with it. Also discussed is the recent advances in the epidemiology, virulence factor and management of community acquired pneumonia in particular.
5. Kloosterman, T. G.; van der Kooi-Pol, M. M.; Bijlsma, J. J.; Kuipers, O. P., The novel transcriptional regulator SczA mediates protection against zinc2+ stress by activation of the zinc2+-resistance gene czcD in Streptococcus pneumoniae. Molecular Microbiology 2007, 65 (4), 1049-63.
This article was the locus of SczA related-research. Through DNAse I footprinting, SczA promoter sequences were discovered, as well as the discovery that SczA is both an activator and a repressor of czcD metal-ion efllux from the cell
6. Martin, J. E.; Edmonds, K. A.; Bruce, K. E.; Campanello, G. C.; Eijkelkamp, B. A.; Brazel, E. B.; McDevitt, C. A.; Winkler, M. E.; Giedroc, D. P., The zinc efflux activator SczA protects Streptococcus pneumoniae serotype 2 D39 from intracellular zinc toxicity. Molecular Microbiology 2017, 104 (4), 636-651.
Article published discussing how zinc intoxication is prevented in S. pneumoniae by expression of the zinc exporter CzcD. Through titration studies, it is shown two zinc ions bind per protomer and through mutagenesis analysis, two binding sites with two distinct affinity terms are discovered.
7. Bou-Abdallah, F.; Giffune, T. R., The thermodynamics of protein interactions with essential first row transition metals. Biochimica et Biophysica Acta 2016, 1860 (5), 879-891.
A review that examines the thermodynamic characterization of metal ion–protein interactions in order to understand the role that metal ions play in living systems. Isothermal titration calorimetry is utilized to study the binding of transition metals to metalloenzymes.
8. Choi, S.; Bird, A. J., zinc'ing sensibly: controlling zinc homeostasis at the transcriptional level. Metallomics 2014, 6 (7), 1198-215.
Critical review of zinc-responsive transcription activators and repressors. Summaries are given about known mechanisms in which 10 common transcription factors sence intracellular zinc levels and how they control these levels through gene expression.
10. Nies, D. H., Efflux-mediated heavy metal resistance in prokaryotes. Federation of European Microbiological Societies Microbiology Reviews 2003, 27 (2-3), 313-339.
Review discussing the mechanisms of action, physiological functions, and distribution of metal-exporting proteins. Specifically focus is placed on CBA efflux pumps, such as cation diffusion facilitators.
11. Turner, A. G. O., S. Y.; Walker, M.; Djoko, K.Y.; McEwan, A. G., Advances in Microbial Physiology, Chapter 5: Transition Metal Homeostasis in Streptococcus Pyogenes and Streptococcus Pneumoniae. Elsevier: 2017; Vol. 70.
Examines the biology, metal starvation, metal overload, and metal ion homeostasis, including how metal ions may be used as future antimicrobials.
12. Versieck, J.; McCall, J. T., Trace Elements in Human Body Fluids and Tissues. Critical Reviews in Clinical Laboratory Sciences 1985, 22 (2), 97-184.
Critical review that seriously investigated and scrutinizes biological metal concentration determination data collected and reported by several PI's. As there is much debate in this area, this review selects values and reports extensively reviewed data concerning trace element levels in the human body.
24. Ramos, J. L.; Martinez-Bueno, M.; Molina-Henares, A. J.; Teran, W.; Watanabe, K.; Zhang, X.; Gallegos, M. T.; Brennan, R.; Tobes, R., The TetR family of transcriptional repressors. Microbiology and Molecular Biology Reviews 2005, 69 (2), 326-56.
Review of TetR family transcription activators and repressors, including identification, regulations, 3D structure, DNA-binding model studies and biotechnology applications.
16. Lambert, M. J., S.; Depauw, S.; David-Cordonnier, M., Targeting Transcription Factors for Cancer Treatment. Molecules 2018, 23 (1479), 1-51.
Discussion of ways to target previously thought "undruggable" targets, including methods in which to by modulating their expressio, block their protein/protein interactions, or by targeting the protein at its DNA-binding site. Includes an overview of drugs currently being used in anticancer therapies.
18. Huang, S. S.; Johnson, K. M.; Ray, G. T.; Wroe, P.; Lieu, T. A.; Moore, M. R.; Zell, E. R.; Linder, J. A.; Grijalva, C. G.; Metlay, J. P.; Finkelstein, J. A., Healthcare utilization and cost of pneumococcal disease in the United States. Vaccine 2011, 29 (18), 3398-412.
Article investigating the effects of S. pneumoniae in terms of hospitilizations, prescriptions written, emergency room visits, deaths and total financial burden.
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