Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening
The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/7/612 |
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| author | Barbara Garofalo Federica Prati Rosa Buonfiglio Isabella Coletta Noemi D’Atanasio Angela Molteni Daniele Carettoni Valeria Wanke Giorgio Pochetti Roberta Montanari Davide Capelli Claudio Milanese Francesco Paolo Di Giorgio Rosella Ombrato |
| author_facet | Barbara Garofalo Federica Prati Rosa Buonfiglio Isabella Coletta Noemi D’Atanasio Angela Molteni Daniele Carettoni Valeria Wanke Giorgio Pochetti Roberta Montanari Davide Capelli Claudio Milanese Francesco Paolo Di Giorgio Rosella Ombrato |
| author_sort | Barbara Garofalo |
| collection | DOAJ |
| description | The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against <i>Klebsiella pneumoniae</i> OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC<sub>50</sub> = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem’s activity in <i>Escherichia coli</i> ATCC BAA-2523 β-lactam resistant strain. Also, <b>ID2</b> showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs. |
| first_indexed | 2024-03-10T10:02:59Z |
| format | Article |
| id | doaj.art-c8323392480c40b1bdc34407531be095 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T10:02:59Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-c8323392480c40b1bdc34407531be0952023-11-22T01:50:18ZengMDPI AGPharmaceuticals1424-82472021-06-0114761210.3390/ph14070612Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput ScreeningBarbara Garofalo0Federica Prati1Rosa Buonfiglio2Isabella Coletta3Noemi D’Atanasio4Angela Molteni5Daniele Carettoni6Valeria Wanke7Giorgio Pochetti8Roberta Montanari9Davide Capelli10Claudio Milanese11Francesco Paolo Di Giorgio12Rosella Ombrato13Angelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAxxam SpA Via Meucci 3, Bresso, 20091 Milan, ItalyAxxam SpA Via Meucci 3, Bresso, 20091 Milan, ItalyAxxam SpA Via Meucci 3, Bresso, 20091 Milan, ItalyConsiglio Nazionale delle Ricerche—Istituto di Cristallografia, Via Salaria—km 29.300, Monterotondo, 00015 Rome, ItalyConsiglio Nazionale delle Ricerche—Istituto di Cristallografia, Via Salaria—km 29.300, Monterotondo, 00015 Rome, ItalyConsiglio Nazionale delle Ricerche—Istituto di Cristallografia, Via Salaria—km 29.300, Monterotondo, 00015 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyAngelini Pharma S.p.A., Global R&D External Innovation, Viale Amelia 70, 00181 Rome, ItalyThe major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against <i>Klebsiella pneumoniae</i> OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC<sub>50</sub> = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem’s activity in <i>Escherichia coli</i> ATCC BAA-2523 β-lactam resistant strain. Also, <b>ID2</b> showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs.https://www.mdpi.com/1424-8247/14/7/612OXA-48β-lactamase inhibitorbacterial resistanceHTS |
| spellingShingle | Barbara Garofalo Federica Prati Rosa Buonfiglio Isabella Coletta Noemi D’Atanasio Angela Molteni Daniele Carettoni Valeria Wanke Giorgio Pochetti Roberta Montanari Davide Capelli Claudio Milanese Francesco Paolo Di Giorgio Rosella Ombrato Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening Pharmaceuticals OXA-48 β-lactamase inhibitor bacterial resistance HTS |
| title | Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening |
| title_full | Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening |
| title_fullStr | Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening |
| title_full_unstemmed | Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening |
| title_short | Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening |
| title_sort | discovery of novel chemical series of oxa 48 β lactamase inhibitors by high throughput screening |
| topic | OXA-48 β-lactamase inhibitor bacterial resistance HTS |
| url | https://www.mdpi.com/1424-8247/14/7/612 |
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