Structure‐Activity Relationships for 5′′ Modifications of 4,5‐Aminoglycoside Antibiotics
Abstract Modification at the 5’’‐position of 4,5‐disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5’’‐modifications of the 4,5‐AGAs and the related 5‐ O‐furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well‐tolerated, but other 4,5‐AGAs require a hydrogen bonding group at the 5’’‐position for maintenance of antibacterial activity. The 5’’‐amino modification resulted in parent‐like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5’’‐formamido group and, to a lesser degree, a 5’’‐ureido group resulted in parent‐like activity without loss of selectivity. These lessons will aid the design of next‐generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
ChemMedChem - 17(2022), 13 |
| Beteiligte Personen: |
Quirke, Jonathan C. K. [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
© 2022 Wiley‐VCH GmbH |
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| Umfang: |
12 |
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| doi: |
10.1002/cmdc.202200120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Modification at the 5’’‐position of 4,5‐disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5’’‐modifications of the 4,5‐AGAs and the related 5‐ O‐furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well‐tolerated, but other 4,5‐AGAs require a hydrogen bonding group at the 5’’‐position for maintenance of antibacterial activity. The 5’’‐amino modification resulted in parent‐like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5’’‐formamido group and, to a lesser degree, a 5’’‐ureido group resulted in parent‐like activity without loss of selectivity. These lessons will aid the design of next‐generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity. | ||
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