Antimicrobial peptides development fits well in my primary research goal, which is to develop novel peptide therapeutics against hard-to-treat bacterial and viral infections. Antimicrobial peptides (AMPs) rapidly (within seconds to minutes) kill bacterial pathogens primarily by a membrane-perturbing (detergent-like) mechanism. They are an untapped resource with broad spectrum of activity paralleled by no other known group of agents to date. Dissecting the unique role of each motif (cationic vs. hydrophobic) of AMP active amphipathic structure in antimicrobial, immune modulatory, and toxic (and other functional) mechanisms will allow optimization of peptide design for improved therapeutic indices.
Rationale. The discovery and early success of antibiotics in the 20th Century led to the misguided view that we were winning the war against infectious diseases. This belief, coupled with stringent requirements for new drug approval by the FDA, has resulted in a drastic reduction in the development of new classes of antibiotics in the last forty years. In the United States, Infections associated with multidrug-resistant (MDR) bacteria result in longer hospital stays, lost productivity, and elevated healthcare cost with increased relative risks of mortality. In addition, antibiotic resistance has a major impact on global health, with infectious diseases remaining among the top three causes of death worldwide. Hence, therapeutics with broader spectrum of efficacy and novel mechanisms of action are urgently needed.
Most AMPs are cationic antimicrobial peptides with an amphipathic structure and represent the first line of defense in diverse species (plants and animals) against a variety of organisms (e.g., bacteria, fungi, parasites, viruses). While it is unclear how select AMPs recognize and kill their viral, parasitic, cancer, and fungal targets, it is well established that most AMPs selectively disrupt bacterial membranes via electrostatic interactions with negatively charged phospholipids on the bacterial surface relative to the more neutral eukaryotic cell surface. In contrast to standard antibiotics, AMPs do not necessarily require metabolic processes for antimicrobial activity, display rapid (seconds or minutes) killing kinetics, and have a low propensity to invoke selection of bacterial resistance (Deslouches et al., 2014). Importantly, the ability of select AMPs to inactivate multiple types of organisms (including cancer cells) indicates the potential for application to a wide range of communicable or polymicrobial diseases. AMPs can also neutralize endotoxins (potential efficacy in septic shock) and may stimulate anti-infective host immune responses. To exploit this remarkable antimicrobial resource, it is imperative that the mechanistic basis for these functional properties be established, with the identification of structural determinants of each of these functional properties informing the design of AMPs for enhanced therapeutic indices.
Over the last two decades, there have been three distinct approaches to AMP development: (1) modification of host AMP sequences for improvement of efficacy, (2) development of high throughput libraries for rapid screening of active peptides, and (3) rational design of de novo engineered AMPs. While important lessons are derived from the first approach, structure-function studies are limited due to the diversity of AMP amino acid compositions; the second approach is rapid, but it does not necessarily allow structure-function predictions; and the last approach reduces diversity in amino acid composition for more controlled structure-function studies to overcome natural limitations to environment and pathogen specificity. I have adopted the latter approach since my initial pre-doctoral experience in Montelaro Laboratory. As a principal investigatory, my goal is to determine the structural determinants of each AMP property for the engineering of application-specific AMPs.