Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i>
The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. <i>Acinetobacter baumannii</i> isolates, despite causing a lower number of infections than Enterobacterales, oft...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-12-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/11/12/1832 |
| _version_ | 1797461802609541120 |
|---|---|
| author | Filomena Sannio Antonella Brizzi Rosita Del Prete Marialuce Avigliano Tiziana Simone Carlotta Pagli Teresa Ferraro Filomena De Luca Marco Paolino Federico Corelli Claudia Mugnaini Jean-Denis Docquier |
| author_facet | Filomena Sannio Antonella Brizzi Rosita Del Prete Marialuce Avigliano Tiziana Simone Carlotta Pagli Teresa Ferraro Filomena De Luca Marco Paolino Federico Corelli Claudia Mugnaini Jean-Denis Docquier |
| author_sort | Filomena Sannio |
| collection | DOAJ |
| description | The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. <i>Acinetobacter baumannii</i> isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant <i>A. baumannii</i> as a “critical priority” for the discovery and development of new antibacterial agents. In a previous work, we identified several series of compounds showing either direct-acting or synergistic activity against relevant Gram-negative species, including <i>A. baumannii.</i> Among these, two pyrazole compounds, despite being devoid of any direct-acting activity, showed remarkable synergistic activity in the presence of a subinhibitory concentration of colistin on <i>K. pneumoniae</i> and <i>A. baumannii</i> and served as a starting point for the synthesis of new analogues. In this work, a new series of 47 pyrazole compounds was synthesized. Some compounds showed significant direct-acting antibacterial activity on Gram-positive organisms. Furthermore, an evaluation of their activity as potential antibiotic adjuvants allowed for the identification of two highly active compounds on MDR <i>Acinetobacter baumannii</i>, including colistin-resistant isolates. This work confirms the interest in pyrazole amides as a starting point for the optimization of synergistic antibacterial compounds active on antibiotic-resistant, Gram-negative pathogens. |
| first_indexed | 2024-03-09T17:24:32Z |
| format | Article |
| id | doaj.art-efe635139d794b8d884a33938c795f96 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T17:24:32Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-efe635139d794b8d884a33938c795f962023-11-24T12:55:10ZengMDPI AGAntibiotics2079-63822022-12-011112183210.3390/antibiotics11121832Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i>Filomena Sannio0Antonella Brizzi1Rosita Del Prete2Marialuce Avigliano3Tiziana Simone4Carlotta Pagli5Teresa Ferraro6Filomena De Luca7Marco Paolino8Federico Corelli9Claudia Mugnaini10Jean-Denis Docquier11Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyLead Discovery Siena S.r.l., Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, ItalyThe diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. <i>Acinetobacter baumannii</i> isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant <i>A. baumannii</i> as a “critical priority” for the discovery and development of new antibacterial agents. In a previous work, we identified several series of compounds showing either direct-acting or synergistic activity against relevant Gram-negative species, including <i>A. baumannii.</i> Among these, two pyrazole compounds, despite being devoid of any direct-acting activity, showed remarkable synergistic activity in the presence of a subinhibitory concentration of colistin on <i>K. pneumoniae</i> and <i>A. baumannii</i> and served as a starting point for the synthesis of new analogues. In this work, a new series of 47 pyrazole compounds was synthesized. Some compounds showed significant direct-acting antibacterial activity on Gram-positive organisms. Furthermore, an evaluation of their activity as potential antibiotic adjuvants allowed for the identification of two highly active compounds on MDR <i>Acinetobacter baumannii</i>, including colistin-resistant isolates. This work confirms the interest in pyrazole amides as a starting point for the optimization of synergistic antibacterial compounds active on antibiotic-resistant, Gram-negative pathogens.https://www.mdpi.com/2079-6382/11/12/1832antibacterialsantibiotic adjuvantcolistinESKAPE bacteriaantibiotic potentiation<i>Acinetobacter baumannii</i> |
| spellingShingle | Filomena Sannio Antonella Brizzi Rosita Del Prete Marialuce Avigliano Tiziana Simone Carlotta Pagli Teresa Ferraro Filomena De Luca Marco Paolino Federico Corelli Claudia Mugnaini Jean-Denis Docquier Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i> Antibiotics antibacterials antibiotic adjuvant colistin ESKAPE bacteria antibiotic potentiation <i>Acinetobacter baumannii</i> |
| title | Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i> |
| title_full | Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i> |
| title_fullStr | Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i> |
| title_full_unstemmed | Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i> |
| title_short | Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant <i>Acinetobacter baumannii</i> |
| title_sort | optimization of pyrazole compounds as antibiotic adjuvants active against colistin and carbapenem resistant i acinetobacter baumannii i |
| topic | antibacterials antibiotic adjuvant colistin ESKAPE bacteria antibiotic potentiation <i>Acinetobacter baumannii</i> |
| url | https://www.mdpi.com/2079-6382/11/12/1832 |
| work_keys_str_mv | AT filomenasannio optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT antonellabrizzi optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT rositadelprete optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT marialuceavigliano optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT tizianasimone optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT carlottapagli optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT teresaferraro optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT filomenadeluca optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT marcopaolino optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT federicocorelli optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT claudiamugnaini optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii AT jeandenisdocquier optimizationofpyrazolecompoundsasantibioticadjuvantsactiveagainstcolistinandcarbapenemresistantiacinetobacterbaumanniii |