New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds
Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bact...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/10/3097 |
| _version_ | 1797497484750094336 |
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| author | Crescenzo Coppa Luca Sorrentino Monica Civera Marco Minneci Francesca Vasile Sara Sattin |
| author_facet | Crescenzo Coppa Luca Sorrentino Monica Civera Marco Minneci Francesca Vasile Sara Sattin |
| author_sort | Crescenzo Coppa |
| collection | DOAJ |
| description | Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model Rel<i><sub>Seq</sub></i>, selected three main chemotypes, and measured their interaction with Rel<i><sub>Seq</sub></i> by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development. |
| first_indexed | 2024-03-10T03:19:52Z |
| format | Article |
| id | doaj.art-1f1274a59fe44197b3929f2e7386b8a6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:19:52Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1f1274a59fe44197b3929f2e7386b8a62023-11-23T12:21:00ZengMDPI AGMolecules1420-30492022-05-012710309710.3390/molecules27103097New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial CompoundsCrescenzo Coppa0Luca Sorrentino1Monica Civera2Marco Minneci3Francesca Vasile4Sara Sattin5Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, 20133 Milano, ItalyDipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, 20133 Milano, ItalyDipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, 20133 Milano, ItalyDipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, 20133 Milano, ItalyDipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, 20133 Milano, ItalyDipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19, 20133 Milano, ItalyAntimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model Rel<i><sub>Seq</sub></i>, selected three main chemotypes, and measured their interaction with Rel<i><sub>Seq</sub></i> by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development.https://www.mdpi.com/1420-3049/27/10/3097AMRpersisters(p)ppGppfragment screeningthermal shift assaySTD-NMR |
| spellingShingle | Crescenzo Coppa Luca Sorrentino Monica Civera Marco Minneci Francesca Vasile Sara Sattin New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds Molecules AMR persisters (p)ppGpp fragment screening thermal shift assay STD-NMR |
| title | New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds |
| title_full | New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds |
| title_fullStr | New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds |
| title_full_unstemmed | New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds |
| title_short | New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds |
| title_sort | new chemotypes for the inhibition of p ppgpp synthesis in the quest for new antimicrobial compounds |
| topic | AMR persisters (p)ppGpp fragment screening thermal shift assay STD-NMR |
| url | https://www.mdpi.com/1420-3049/27/10/3097 |
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