PNA-STAMPs: Versatile, Potent and Targeted Antibiotics

Project Summary There is a critical need to develop therapies targeting Streptococcus pneumoniae (Spn): a major human pathogen contributing to global morbidity and mortality. We propose to use Specifically Targeted Anti-Microbial Peptides (STAMPs), where a broad spectrum anti-microbial peptide (AMP) is fused to a Spn secreted peptide. The former will provide anti-microbial activity, while the latter will impart selectivity of this activity at the taxonomic level or increase efficacy of the AMP. This project builds on preliminary data where we show that human beta- defensin 3 is ineffective in killing Spn. In contrast, a fusion of this AMP to a Spn cell-cell communication peptide resulted in a peptide that eliminated >95% of Spn in culture. Further, we propose an innovative way to produce STAMP peptides, where we will deploy a “molecular velcro” technology based on complementary peptide nucleic acid (PNA) adapters. These PNA adapters are connected to the ends of independent targeting and AMP domains, allowing facile assembly and screening of PNA-STAMP libraries. Conclusion of the proposed work will introduce species-specific antimicrobials for Spn targeting and develop a conceptual and technical platform for the development of Gram-positive antimicrobials.