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.
