Background. The emergence of bacterial strains resistant to available antibiotic armamentarium is nowadays a pressing issue in clinical therapy. Among the several mechanisms of bacterial resistance, the rapid evolution and spread of carbapenemases, β-lactamases (BLs) with versatile hydrolytic capacities able to inactivate last resort carbapenems, represents a menace in treating highly resistant infections. [1-3] Carbapenem-resistant Enterobacteriaceae (CREs), reported with increased frequency, are progressively spreading throughout the World thus leaving no effective antibiotics. [1-3] In particular CREs overexpressing Metallo beta-lactamases (MBLs; i.e. NDM-1, VIM-2, IMP-1) are high-priority target pathogens for the development of novel antibacterials. Our studies focused on NDM-1: its substrate promiscuity, its resistance to available drugs, the easiness of variants appearance and transferability make NDM-1 one of the most worrisome BLs. [2] Moreover, respect to serine β-lactamases, no inhibitors for any MBLs are currently available in therapy. Materials/methods. Looking for new potential MBLs inhibitors we performed a structure-based in silico screening of commercially available library using FLAP, and identified several non β-lactam derivatives as promising candidates active against our target New Delhi metallo-beta-lactamase-1 NDM-1. Candidates were validated in vitro and investigated for their mechanism of inhibition. Results. The binding affinities of the highest scoring hits revealed, for several of them, micromolar inhibitory activity towards NDM-1. Among molecules selected for targeting NDM-1 few demonstrated an activity comparable to that provided by known inhibitors (Ki for the best-selected inhibitor equal to 0.72 μM; ). The identified inhibitors all share common non-covalent, competitive inhibition mechanism vs NDM-1. Conclusion. For the best ones, studies for improving their affinity and to investigate their potential to synergize beta-lactam antibiotics are ongoing. X-ray crystallography studies are now in progress to confirm our docking prediction and to deeply investigate the structural requirement necessary for proficuous hit to lead generation. Figure 1 References [1] Jean-Marie Frère, Eric Sauvage and Frédéric Kerff. “From “An enzyme able to destroy penicillin » to carbapenemases: 70 years of beta-lactamase misbehavior” Current Drug Targets, (2016). Volume 16. (E-pub ahead of print). [2] Robert A. Bonomo. “New Delhi Metallo-β-Lactamase and Multidrug Resistance: A Global SOS?”Clin Infect Dis. (2011) 52 (4): 485-487 [3] Donatella Tondi, Alberto Venturelli, Richard Bonnet, Cecilia Pozzi, Brian K Shoichet and Maria Paola Costi. “Targeting Serine Beta lactamases with a novel broad spectrum boronic acid”. Journal Medicinal Chemistry. (2014)

Structure based drug design: the discovery of novel inhibitors active against New Delhi Metallo-β-lactamase-1 / Cendron, Laura; Spyrakis, Francesca; Marcoccia, Francesca; Cross, Simon; Bellio, Pierangelo; Celenza, Giuseppe; Perilli, Mariagrazia; Tondi, Donatella. - (2017). ((Intervento presentato al convegno 13th beta-lactamase Meeting tenutosi a santo Stefano di Sessanio nel 16-19 June 2017.

Structure based drug design: the discovery of novel inhibitors active against New Delhi Metallo-β-lactamase-1

SPYRAKIS, FRANCESCA;TONDI, Donatella
2017-01-01

Abstract

Background. The emergence of bacterial strains resistant to available antibiotic armamentarium is nowadays a pressing issue in clinical therapy. Among the several mechanisms of bacterial resistance, the rapid evolution and spread of carbapenemases, β-lactamases (BLs) with versatile hydrolytic capacities able to inactivate last resort carbapenems, represents a menace in treating highly resistant infections. [1-3] Carbapenem-resistant Enterobacteriaceae (CREs), reported with increased frequency, are progressively spreading throughout the World thus leaving no effective antibiotics. [1-3] In particular CREs overexpressing Metallo beta-lactamases (MBLs; i.e. NDM-1, VIM-2, IMP-1) are high-priority target pathogens for the development of novel antibacterials. Our studies focused on NDM-1: its substrate promiscuity, its resistance to available drugs, the easiness of variants appearance and transferability make NDM-1 one of the most worrisome BLs. [2] Moreover, respect to serine β-lactamases, no inhibitors for any MBLs are currently available in therapy. Materials/methods. Looking for new potential MBLs inhibitors we performed a structure-based in silico screening of commercially available library using FLAP, and identified several non β-lactam derivatives as promising candidates active against our target New Delhi metallo-beta-lactamase-1 NDM-1. Candidates were validated in vitro and investigated for their mechanism of inhibition. Results. The binding affinities of the highest scoring hits revealed, for several of them, micromolar inhibitory activity towards NDM-1. Among molecules selected for targeting NDM-1 few demonstrated an activity comparable to that provided by known inhibitors (Ki for the best-selected inhibitor equal to 0.72 μM; ). The identified inhibitors all share common non-covalent, competitive inhibition mechanism vs NDM-1. Conclusion. For the best ones, studies for improving their affinity and to investigate their potential to synergize beta-lactam antibiotics are ongoing. X-ray crystallography studies are now in progress to confirm our docking prediction and to deeply investigate the structural requirement necessary for proficuous hit to lead generation. Figure 1 References [1] Jean-Marie Frère, Eric Sauvage and Frédéric Kerff. “From “An enzyme able to destroy penicillin » to carbapenemases: 70 years of beta-lactamase misbehavior” Current Drug Targets, (2016). Volume 16. (E-pub ahead of print). [2] Robert A. Bonomo. “New Delhi Metallo-β-Lactamase and Multidrug Resistance: A Global SOS?”Clin Infect Dis. (2011) 52 (4): 485-487 [3] Donatella Tondi, Alberto Venturelli, Richard Bonnet, Cecilia Pozzi, Brian K Shoichet and Maria Paola Costi. “Targeting Serine Beta lactamases with a novel broad spectrum boronic acid”. Journal Medicinal Chemistry. (2014)
13th beta-lactamase Meeting
santo Stefano di Sessanio
16-19 June 2017
Cendron, Laura; Spyrakis, Francesca; Marcoccia, Francesca; Cross, Simon; Bellio, Pierangelo; Celenza, Giuseppe; Perilli, Mariagrazia; Tondi, Donatella
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1141377
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