The extensive use of beta-lactam antibiotics has created major resistance problems leading to increased morbidity, mortality and health-care costs. Resistance is most often mediated by eta-lactamases (BLs), which have emerged in both Gram-positive and Gram-negative bacteria [1,2]. Medicinal chemists have introduced eta-lactam-based molecules that inhibit or are stable to their action. These molecules are themselves eta-lactams, making it easier for bacteria to respond by adapting previously evolved mechanisms. Many bacteria are now resistant to these anti-resistance compounds. Thus there is a growing need for new broad-spectrum eta-lactamases inhibitors in general and especially against carbapenemases (i.e KPC, NDM-1, VIM)[3,4]. Their substrate promiscuity, their resistance to available drugs, the easiness of variants appearance and transferability make carbapenemases the most worrisome BLs [2]. Focusing on the de novo, non beta-lactam like derivatives we identified, through a structure-based in silico screening of commercially available library using FLAP, several promising candidates active against class A and class B carbapenemases. The binding affinities of the high scoring hits were measured in vitro revealing, for some of them, low micromolar affinity towards BLs. To investigate the potential of these compounds to reverse antibiotic resistance, we are undertaking antimicrobial activity studies in bacterial cell culture. The ability of novel compounds to synergize antibiotics against pathogenic resistant bacteria, as well as their ability to evade those mechanisms normally involved in resistance to eta-lactam-based inhibitors are now under evaluation. Moreover, since our inhibitors are novel, non eta-lactam based, we expect them to do not up-regulate eta-lactamase expression in cell culture. 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. Keywords: carbapenemases resistance, SBDD, in silico screening, enzyme inhibition, antimicrobial activity, x-ray crystallography

DESIGNING NOVEL INHIBITORS FOR CARBAPENEMASES: A MULTIDISCIPLINARY APPROACH / Spyrakis, Francesca; Bellio, Pierangelo; Vicario, Mattia; Cendron, Laura; Marcoccia, Francesca; Perilli, Mariagrazia; Cruciani, Gabriele; Costi, Maria Paola; Celenza, Giuseppe; Tondi, Donatella. - (2016). ((Intervento presentato al convegno XXIV National Meeting in Medicinal Chemistry tenutosi a Perugia Italy nel 11-14 Settembre 2016.

DESIGNING NOVEL INHIBITORS FOR CARBAPENEMASES: A MULTIDISCIPLINARY APPROACH

SPYRAKIS, FRANCESCA;COSTI, Maria Paola;TONDI, Donatella
2016-01-01

Abstract

The extensive use of beta-lactam antibiotics has created major resistance problems leading to increased morbidity, mortality and health-care costs. Resistance is most often mediated by eta-lactamases (BLs), which have emerged in both Gram-positive and Gram-negative bacteria [1,2]. Medicinal chemists have introduced eta-lactam-based molecules that inhibit or are stable to their action. These molecules are themselves eta-lactams, making it easier for bacteria to respond by adapting previously evolved mechanisms. Many bacteria are now resistant to these anti-resistance compounds. Thus there is a growing need for new broad-spectrum eta-lactamases inhibitors in general and especially against carbapenemases (i.e KPC, NDM-1, VIM)[3,4]. Their substrate promiscuity, their resistance to available drugs, the easiness of variants appearance and transferability make carbapenemases the most worrisome BLs [2]. Focusing on the de novo, non beta-lactam like derivatives we identified, through a structure-based in silico screening of commercially available library using FLAP, several promising candidates active against class A and class B carbapenemases. The binding affinities of the high scoring hits were measured in vitro revealing, for some of them, low micromolar affinity towards BLs. To investigate the potential of these compounds to reverse antibiotic resistance, we are undertaking antimicrobial activity studies in bacterial cell culture. The ability of novel compounds to synergize antibiotics against pathogenic resistant bacteria, as well as their ability to evade those mechanisms normally involved in resistance to eta-lactam-based inhibitors are now under evaluation. Moreover, since our inhibitors are novel, non eta-lactam based, we expect them to do not up-regulate eta-lactamase expression in cell culture. 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. Keywords: carbapenemases resistance, SBDD, in silico screening, enzyme inhibition, antimicrobial activity, x-ray crystallography
XXIV National Meeting in Medicinal Chemistry
Perugia Italy
11-14 Settembre 2016
Spyrakis, Francesca; Bellio, Pierangelo; Vicario, Mattia; Cendron, Laura; Marcoccia, Francesca; Perilli, Mariagrazia; Cruciani, Gabriele; Costi, Maria Paola; Celenza, Giuseppe; Tondi, Donatella
DESIGNING NOVEL INHIBITORS FOR CARBAPENEMASES: A MULTIDISCIPLINARY APPROACH / Spyrakis, Francesca; Bellio, Pierangelo; Vicario, Mattia; Cendron, Laura; Marcoccia, Francesca; Perilli, Mariagrazia; Cruciani, Gabriele; Costi, Maria Paola; Celenza, Giuseppe; Tondi, Donatella. - (2016). ((Intervento presentato al convegno XXIV National Meeting in Medicinal Chemistry tenutosi a Perugia Italy nel 11-14 Settembre 2016.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1110741
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