One of the overarching objectives of our laboratory is to design and develop new drugs to fight resistant microbes. We achieve this using a combination of computational techniques and wet lab experimental methodology. The drug discovery aspects of our research involve working with candidate agents (small molecules, peptides, polymers, etc.) to identify those with potent activity against bacterial pathogens that cause deadly human infections. This is a tedious process that involves a combination interdisciplinary work to initially characterize the biological profile of active compounds and finally validate the molecular targets within bacterial cells. This process also involves ensuring the safety of mammalian cells by assessing potential cytotoxicity as shown in the example images below.
HeLa cell culture - bright field image.
HeLa cell culture stained with propidium iodide; a fluorophore that stains membrane compromised dead/dying cells.
HeLa cell culture - overlay of the bright field and propidium iodide-stained images showing the dead/dying cells (red).
HeLa cell culture stained with two fluorophores, DAPI (blue) for indicating live cells & propidium iodide (red) indicating dead/dying cells.
A significant part of the work in our laboratory involves biochemical experiments aimed at understanding drug-target interactions at molecular level. We utilize the latest biophysical techniques such as Microscale thermophoresis (MST), Temperature Induces Intensity Change (TRIC), Spectra shift, and fluorescence-based assays to define binding affinities between small molecules and their potential cellular targets. We also utilize enzyme inhibition assays to identify compounds that inhibit the activity of specific enzymes that facilitate antibiotic resistance in bacteria.
A section of our laboratory focuses on experiments involving microbiology. We study several species of bacteria including, Escherichia coli, Bacillus anthracis, Staphylococcus aureus and Pseudomonas aeruginosa. We are investigating different resistance elements in these bacterial pathogens with the objective of developing agents that can terminate/block the onset of resistance under clinical settings. This work involves genetic manipulations to study the effects of different genes to the antibiotic response by bacteria.
Several projects in the lab are dependent on validating the target of a candidate drug. We will be using small molecule chemical probe to identify molecular targets for such compounds within bacterial cells. This strategy involves designing and using targeted probes in biological environments and will include techniques like bio-orthogonal click conjugation chemistry, photoaffinity labeling, and cross-linking experiments.