Structure-Activity Relationships for 5′′ Modifications of 4,5-Aminoglycoside Antibiotics
- Citation:
- Quirke, J. C. K., G. C. Sati, A. Sonousi, M. Gysin, K. Haldimann, E. C. Böttger, A. Vasella, S. N. Hobbie, and D. Crich, "Structure-Activity Relationships for 5′′ Modifications of 4,5-Aminoglycoside Antibiotics", ChemMedChem, vol. 17, issue 13: John Wiley & Sons, Ltd, pp. e202200120, 2022.
Abstract:
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.