Friday, October 26, 2018

OSCAR Student Mosufa Zainab Studies the Inhibition of Acinetobacter Baumannii and Klebsiella Pneumoniae 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (IspC)

My time as an undergraduate researcher has been one of the most gratifying experiences of my academic career. My passion for research stems from my deep-rooted fascination with an understanding of the natural world, specifically through the lens of biology and chemistry. As a student, learning about biochemical changes in living organisms was like entering into a new universe, full of adventures and discoveries. However, that sense of discovery was confined to the space of classroom and comprised solely of the facts in textbooks. Research has allowed me to experience science in its truest form - where facts are in the phase of discovery.

For my Undergraduate Research Scholars Program 2018 project, I am currently working in the Couch Lab at the Institute of Advanced Biomedical Research. My project focuses on the development of novel antibiotics targeting the non-mevalonate pathway (MEP). Given the rapid rise in antibiotic resistant pathogens, our work seeks to combat this growing threat. Today, antibiotic resistance has become a leading cause of death and disease worldwide. Each year, within the United States alone, at least two million people are infected with drug-resistant bacteria. Of those documented cases, approximately 23,000 prove to be fatal. If left unchecked, antibiotic resistant pathogens pose a catastrophic threat to the human population. Among all of the documented antibiotic resistant bacterial strains, Acinetobacter baumannii and Klebsiella pneumonia are particularly alarming. They comprise two of the ESKAPE pathogens, a group of multidrug resistant pathogens that are the leading cause of nosocomial infections worldwide.

Since current antibiotic targets within these bacterial strains no longer remain viable options, this project focuses on inhibition of isoprenoid production in pathogens in order to develop novel antibiotics. Isoprenoids are integral for many cellular functions such as membrane stability and aerobic respiration. While Isoprenoids are essential in both mammalian and bacterial cells, the means through which they are synthesized varies between organisms. Mammals synthesize Isoprenoids via the mevalonate pathway while bacteria synthesize them through the non-mevalonate pathway. The absence of the non-mevalonate pathway in mammals and the fundamental need of Isoprenoids, within the bacterial organisms, make the non-mevalonate pathway a viable target for drug development.

In an effort to exploit the unique bacterial isoprenoid biosynthetic pathway, compounds designed to inhibit the first committed enzyme of the pathway, 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (IspC) in both Acinetobacter baumannii and Klebsiella pneumoniae, were assayed against the enzyme. Using known IspC inhibitors, Fosmidomycin and FR900098, as a scaffold, rationally designed compounds were provided by Dr. Cynthia Dowd at George Washington University. On a weekly basis, I expressed, purified, and assayed IspC derived from Acinetobacter baumannii and Klebsiella pneumoniae against rationally designed inhibitory compounds. Those compounds which were found to reduce enzymatic activity to less than 10% were selected for half maximal inhibitory concentration (IC50) determination.

Throughout my time spent in the Couch lab, I have learned a lot about the research process, including preserving in spite of setbacks, and savoring the accomplishment that comes from obtaining reproducible results. The effort to develop novel antibiotics is a daunting task, and yet is absolutely necessary to halt the growing threat of infection from antibiotic resistant bacteria. While I realize there is still a great deal of work to be done, I feel honored to have played a small part in moving the scientific community forward and helping in the design of a new class of antibiotics.