期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 28, 期 36, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202200883
关键词
aminoglycoside antibiotics; antimicrobial resistance; catalytic oxidation; epimerization; regioselective modification
资金
- European Research Council [694610]
- Projekt DEAL
- European Research Council (ERC) [694610] Funding Source: European Research Council (ERC)
The emergence of antimicrobial resistance poses a serious threat to patients infected by multidrug-resistant pathogens. Researchers have developed a new method to modify the structure of antibiotics, creating two novel antibiotic candidates that can overcome bacterial resistance.
The continuous emergence of antimicrobial resistance is causing a threat to patients infected by multidrug-resistant pathogens. In particular, the clinical use of aminoglycoside antibiotics, broad-spectrum antibacterials of last resort, is limited due to rising bacterial resistance. One of the major resistance mechanisms in Gram-positive and Gram-negative bacteria is phosphorylation of these amino sugars at the 3'-position by O-phosphotransferases [APH(3')s]. Structural alteration of these antibiotics at the 3'-position would be an obvious strategy to tackle this resistance mechanism. However, the access to such derivatives requires cumbersome multi-step synthesis, which is not appealing for pharma industry in this low-return-on-investment market. To overcome this obstacle and combat bacterial resistance mediated by APH(3')s, we introduce a novel regioselective modification of aminoglycosides in the 3'-position via palladium-catalyzed oxidation. To underline the effectiveness of our method for structural modification of aminoglycosides, we have developed two novel antibiotic candidates overcoming APH(3')s-mediated resistance employing only four synthetic steps.
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