IN SIGNO Project

FRRB Project 3423223 - Identification of Novel molecules Supporting the Impact of ß-lactams against clinically-relevant Gram-Negative multidrug resistant Organisms

The Coordinator of the project is Ospedale San Raffaele S.r.l. IRCCS. The Lead Principal Investigator of the project is Prof. Nicasio Mancini.

PROJECT SUMMARY

Antimicrobial resistance (AMR) largely predates COVID-19 and will still continue to affect the humankind even when the ongoing SARS-CoV-2 pandemic will be over. A prompt action to limit the impact of this largely unmet medical need is mandatory, and it includes both the preservation of existing antibiotics and the identification of novel molecules. In this project, we aim at discovering - through a biological activity-guided screening - novel antibiotic adjuvants, which could be used in combination with ß-lactams against multidrug-resistant Gram-negative (MDR-GN) bacteria. Five clinically-relevant models of ß-lactam resistance in MDR-GN will be selected, including an extended-spectrum ß-lactamase-producing Enterobacterales, three models of carbapenemase-producing Enterobacterales, and a carbapenemase-producing Pseudomonas aeruginosa. A filamentous actinomycetes- and filamentous fungi-based microbial library (containing 39,000 crude extracts) and a chemical library of 9,500 pure compounds of known structures will be used for the screening. Selected molecules, able to restore the activity of ß-lactams against the resistant isolates will be identified, characterized, and further improved using both in vitro and in silico approaches. The most promising candidates will then be evaluated on a wide panel of MDR-GN clinical isolates and tested for their cytotoxicity on different eukaryotic cells, thus paving the way for their possible preclinical development and future medical use.