University of Pittsburgh Environment & Occupational Health and Microbiology & Molecular Genetics, Pittsburgh, PA 15219

Berthony Deslouches 2018 research objectives update

AMP optimization, research objectives 2018

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/antimicrobials on the microbiome, and (3) to develop a global health program in Haiti (microbiome, combatting infections, etc.)

AMP optimization, research objectives 2018

. The human AMP LL37. Composed of 14 different amino acids arranged in an imperfect amphipathic helix (helical wheel), LL37 (as many other AMPs) has evolved to display multiple functions. Fitting the structural determinants of all these functions in a single molecule may limit the potential for complete optimization of antibiotic activity, which largely explains why AMP structure may not be as potent in biological matrices as conventional antibiotics. LL37 is currently in clinical trial as an anti-tumor agent delivered intratumorally12; µH, hydrophobic moment, a measure of amphipathicity. AMP limitations can be overcome by design optimization. (A) helical wheel projections of engineered AMPs LBU2, WLBU2, and WR12 modeled to form idealized amphipathic structures; MRSA was treated with LL37 and the indicated peptides in (B) phosphate buffer (PB) or (C) phosphate buffered saline (PBS) and bacterial counts in CFU/mL determined by dilution and growth on LB agar plates. LL37 displays similar activity in PB to LBU2 (B), made of just 2 amino acids (Arg and Val). However, LL37 and LBU2 are sensitive to saline (C). In sharp contrast, Trp-rich peptides WR12 and WLBU2 (derived from LBU2 by 3 Trp substitutions) are not affected by the presence of saline, proving that susceptibility to salt can be overcome by design optimization. Arrows indicate directions of µH.

Research objectives 2018: I have a 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 antimicrobial therapeutics on the microbiome.
I have 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). I initially 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. We need 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. To be continued/updated…

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