Antimicrobial resistance is a global crisis. There is an urgent need for new antibiotics as well as strategies to combat resistance, particularly in hospital settings where drugs of last resort like daptomycin (DAP) are becoming ineffective. A critical step in the development of such strategies lies in understanding the evolutionary trajectories responsible for resistance and the identification of proteins or biochemical pathways that can be good targets for the design of novel treatment strategies and co-drugs. To this end, the lab uses a combinatorial approach that involves experimental evolution, genomics, biophysical and biochemical techniques to delineate the molecular basis of antimicrobial resistance. This holistic approach enables the deconstruction of complex mechanisms leading to resistance. One of the focuses in the lab is to understand the basis for daptomycin resistance in enterococci which are a type of ESKAPE pathogen that cause over 66,000 infections per year in the United States. Experimental evolution of Enterococcus faecalis to DAP led to the identification of mutations in the LiaFSR 3-component system and the discovery of a novel downstream target, LiaX whose upregulation was required for resistance. Physico-chemical studies led to the determination of the crystal structure of LiaR that regulates transcription in response to daptomycin mediated membrane stress. Biochemical studies with mutants helped determine the role of specific LiaR mutations in conferring DAP resistance. Both these proteins serve as putative targets for drug discovery.
Other organisms of interest to the lab include E. faecium, Acinetobacter baumannii, Pseudomonas aeruginosa, Nocardia and Francisella.
In addition to determining the molecular mechanisms leading to resistance, the lab is also interested in studying microbial interactions. With the help of microfluidic techniques to create spatially segregated emulsion systems, we wish to understand bacterial interactions and the evolutionary processes that lead to such relations.
For more information and details of the projects going on in the Shamoo lab, please view the “Current lab members” and Shamoo Lab publications pages.