Research objectives 2018 update: My goals are (1) to develop peptide-based therapeutics against multidrug-resistant pathogens, (2) to investigate the impact of environmental toxicants on the microbiome and host-pathogen interactions, (3) to develop a global health program between University of Pittsburgh and Haiti related to the first two objectives (microbiome, combatting infections, etc.)
Research objectives 2018: I have a rich multidisciplinary expertise in antimicrobial therapeutics, microbiology, biochemistry, immunology, toxicology, and pathology. This extensive experience enables me to address two different (although related) problems: multidrug resistance and the impact of environmental toxicants on the microbiome and host defense.
I previously investigated the structure-function relationship of antimicrobial peptides (AMPs) using de novo-engineered cationic AMPs (eCAPs) and demonstrated that AMP structure could be optimized to overcome many of the limitations of natural AMPs (e.g., reduced activity in acidic pH and serum salt concentrations). During my graduate and postdoctoral training, I enhanced the design of an initial series of Montelaro-engineered AMPs and demonstrated systemic efficacy against P. aeruginosa, using animal models of in vivo toxicity and sepsis treatment. The data led to six first-author papers in addition to over a dozen collaborative publications. Despite the success of these eCAPs, this was the first trial of optimization of the engineered AMPs, and these peptides are still being engineered mostly through trial and error. Considerable effort is required to completely investigate the potential of this new source of therapeutics. However, my vision goes far beyond the development of AMPs as antimicrobials as described in the following aims.
Aim 1. To establish a rational framework for the design of peptide-based therapeutics. I wish to establish a rational framework for peptide design for specific clinical applications against multidrug-resistant pathogens. I will expand AMP engineering to the design of peptide-based therapeutics of enhanced pharmacological properties with the goal to overcome hard-to-treat bacterial infections as well as viral and cancer disease. I intend to use biochemical methods to enhance their pharmacological properties using D-enantiomerization, cyclization, and “peptoidization” (e.g., shifting the amino acid side chain from the alpha to the adjacent or β-carbon). This aim will be supported by my new R01 award from NIGMS.
Aim 2. To elucidate the impact of environmental toxicants and antimicrobial therapeutics on the microbiome and host-pathogen interactions. This aim addresses the hypothesis that environmental toxicants have a combined effect on the host and the microbiota (including potential pathogens), which co-exist in the same ecosystem. Comparison of the impact of antibiotic and AMP therapy on the microbiome will be an important consideration. This work is in collaboration with the Center for Microbiome and Medicine.
Aim 3. To develop appropriate animal disease models addressing specific therapeutic applications and environmental impact on host defense. This aim establishes the connection between the first two objectives. To further advance the development of peptide-based therapeutics and examine the impact of environmental toxicants on the microbiome and host defense, I will seek to develop several animal models such as murine exposure to toxicants and/or respiratory pathogens as well as infection treatment models for specific applications (sepsis, trauma, or surgical site infections). I will seek a grant from the Department of Defense (DOD) to fund these specialized infection projects. I also have an interest in developing a global health program involving the University of Pittsburgh and Haiti as a long-term goal.