The spread of antimicrobial resistance represents an enormous global health crisis, with infections caused by multi-drug resistant bacteria contributing to >1 million deaths per year. 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. The aim of the IN SIGNO project, recently funded by Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia), is discovering -through a biological activity-guided screening- novel antibiotic adjuvants, which could be used in combination with β-lactams against multidrug-resistant Gram-negative (MDR-GN) bacteria. To this purpose, we first selected five clinically-relevant models of β-lactam resistance in MDR-GN: an extended-spectrum β-lactamase-producing Escherichia coli strain (CTX-M type), three carbapenemase-producing Klebsiella pneumoniae strains (KPC-1, KPC-31, and VIM-1 types), and a VIM-2-producing Pseudomonas aeruginosa. Then, we proceed with the screening of a filamentous actinomycetes/fungi-based microbial library (39,000 crude extracts) and of a chemical library (9,500 pure compounds), to select molecules able to restore the activity of β-lactams against the resistant isolates previously described. The three most promising candidates thus far selected are natural products, since no hits have been identified yet from chemical library. If their activity is confirmed, we will progress in elucidating the chemical structure of the putative inhibitors, test their in vitro and in silico interaction with β-lactamases to better define their mode of action, evaluate activity on a wider panel of MDR-GN clinical isolates, and assess their cytotoxicity on different eukaryotic cells.
The IN SIGNO project: Identification of novel molecules supporting the impact of β-lactams against clinically-relevant Gram-negative multidrug resistant organisms
F. Berini
;F. Marinelli;G. Molla;M. Crespi;S. Gazzola;L. Piubelli;E. Binda;A. Baj;N. Mancini
2023-01-01
Abstract
The spread of antimicrobial resistance represents an enormous global health crisis, with infections caused by multi-drug resistant bacteria contributing to >1 million deaths per year. 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. The aim of the IN SIGNO project, recently funded by Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia), is discovering -through a biological activity-guided screening- novel antibiotic adjuvants, which could be used in combination with β-lactams against multidrug-resistant Gram-negative (MDR-GN) bacteria. To this purpose, we first selected five clinically-relevant models of β-lactam resistance in MDR-GN: an extended-spectrum β-lactamase-producing Escherichia coli strain (CTX-M type), three carbapenemase-producing Klebsiella pneumoniae strains (KPC-1, KPC-31, and VIM-1 types), and a VIM-2-producing Pseudomonas aeruginosa. Then, we proceed with the screening of a filamentous actinomycetes/fungi-based microbial library (39,000 crude extracts) and of a chemical library (9,500 pure compounds), to select molecules able to restore the activity of β-lactams against the resistant isolates previously described. The three most promising candidates thus far selected are natural products, since no hits have been identified yet from chemical library. If their activity is confirmed, we will progress in elucidating the chemical structure of the putative inhibitors, test their in vitro and in silico interaction with β-lactamases to better define their mode of action, evaluate activity on a wider panel of MDR-GN clinical isolates, and assess their cytotoxicity on different eukaryotic cells.
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