Late-Stage Modification of Aminoglycoside Antibiotics Overcomes Bacterial Resistance Mediated by APH(3') Kinases.

Chemistry (Weinheim an der Bergstrasse, Germany) 2022 Jun 27

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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. © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

Citation

Andreas A Bastian, Maria Bastian, Manuel Jäger, Mark Loznik, Eliza M Warszawik, Xintong Yang, Nabil Tahiri, Peter Fodran, Martin D Witte, Anne Thoma, Jens Köhler, Adriaan J Minnaard, Andreas Herrmann. Late-Stage Modification of Aminoglycoside Antibiotics Overcomes Bacterial Resistance Mediated by APH(3') Kinases. Chemistry (Weinheim an der Bergstrasse, Germany). 2022 Jun 27;28(36):e202200883