Novel peptide-based therapeutics for elimination of antimicrobial resistance
Antimicrobial resistance (AMR) occurs when microbial pathogens (bacteria, viruses, fungi and parasites) no longer respond to antimicrobial medications and currently is one of the greatest global health challenges. Dealing with AMR requires dedicated approaches for each pathogen, particularly for the bacteria that belong to the so-called ESCAPE group of pathogens (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa) which according to data from 2019, are responsible for more than 250,000 caused deaths related to antimicrobial resistance. The field of peptide-drug conjugates (PDC) has grown significantly over the past decades and recently some PDC-based antimicrobials have been recognized as a promising class of antimicrobial reagents to combat the ongoing global threat of multidrug-resistant bacteria. Within PANTERA, we will focus on the design and synthesis of antimicrobial PDCs with improved stability, selectivity and efficacy against reference/resistant Escherichia coli strains. Special emphasis will be placed on the conjugation of peptides with other molecular entities (porphyrins) in order to improve conjugate therapeutic properties and increase resistance to enzymatic degradation. By using a various activation strategies on a solid support, several N- and C-terminal conjugates will be obtained by combining four peptides (AA16, G3, LTP3 and PW1) that selectively recognize outer membrane of the gram-negative bacteria, two antimicrobial porphyrins (MPIX and PPIX) and one linker (O2Oc). All conjugates will be characterized by advanced characterization methods (spectroscopy, chromatography, mass spectrometry and biophysical analyses), followed by in vitro antimicrobial activity testing. In this way, the "PANTERA" project will contribute to fill the current gap in the antimicrobial pipeline with new entries that can significantly advance the antimicrobial therapy of the future.