Synthesis of New DltA Inhibitors and Their Application as Adjuvant Antibiotics to Re-Sensitize Methicillin-Resistant <i>Staphylococcus aureus</i>
The synthesis of a new acyclic and cyclic series of D-Ala-AMP analogues was reported. Chemical modifications were introduced on the carbohydrate, the sulfamate linker, and/or the amino-acid <i>N</i>-terminal moiety in order to increase <i>in vivo</i> stability and cell permea...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/12/2569 |
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| Summary: | The synthesis of a new acyclic and cyclic series of D-Ala-AMP analogues was reported. Chemical modifications were introduced on the carbohydrate, the sulfamate linker, and/or the amino-acid <i>N</i>-terminal moiety in order to increase <i>in vivo</i> stability and cell permeability. These new compounds were evaluated <i>in vitro</i> as DltA inhibitors and also <i>in vivo</i> as adjuvant antibiotics to re-sensitize methicillin-resistant <i>Staphylococcus aureus</i>. Indeed, we showed that seven nucleosides containing either a fluorine atom, an azido group, a difluorophosphonylated allylic ether moiety onto the 2′-position, or a sulfamate and a triazole as the sulfamate linker had moderate to excellent IC<sub>50</sub> values. Among all these new DltA inhibitors, two molecules functionalized by the fluorinated ether or the sulfamide linker were able to efficiently re-sensitize MRSA to imipenem. Quantification of D-alanyl esters confirmed that these two compounds reduced the level of bacterial cell wall D-alanyl residues by 50% and 80%. |
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| ISSN: | 1420-3049 |