Toward Overcoming Staphylococcus aureus Aminoglycoside Resistance Mechanisms with a Functionally Designed Neomycin Analogue

Abstract

Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(L)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC 50 and MIC 90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.

Pyridoxal-5′-phosphate-dependent enzyme GenB3 Catalyzes C-3′,4′-dideoxygenation in gentamicin biosynthesis

“…Since GenP, GenB3, and GenB4 catalyze C-3′,4′-dideoxygenation, they have the potential to be applied in combinatorial biosynthesis of C-3′,4′-dideoxygenation containing semi-synthetic antibiotics, such as dibekacin and arkekacin [ 36 ], to develop novel drugs against life-threatening pathogens and to yield an improved safety profile [ 37 ]. Because C-3′, C-4′, and C-6′ are frequently used chemical modification sites for semi-synthesis of AGAs [ 38 – 40 ], GenP, GenB3, and GenB4 may be used for combined chemical and enzymatic syntheses of promising therapeutic leads.…”

N6′, N6′′′, and O4′ Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity

“…Overall, the exploration of other substituents on N6′ of the neomycin class of 4,5-AGAs may be a fruitful avenue for future explorations both alone and in combination with other recently described modifications known to enhance antibacterial activity. 8,41–49 …”

“…5,34,40 Several studies have reported in recent years on the synthesis of improved neomycin derivatives with reduced susceptibility to AMEs, including derivatives of the 6′-amino group. 8,41–49 As demonstrated originally by a Schering-Plough group 45,46 and subsequently exploited by ISIS, 41 and Achaogen 50 6′-amino AGAs can be modified by alkylation of the 6′-amino group to overcome the effects of AAC(6′) AMEs. However, the effects of all these modifications on binding to the eukaryotic mitochondrial ribosomes and, consequently, on the ototoxicity of such derivatives are not known.…”

Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

“…This synthetic strategy relied on a novel application of the chemoselective Garegg-Samuelsson deoxygenation reaction in combination with N 1-modifications via oxazolidinones for efficient access to promising antibiotics analogues. 52 Both NEO and PAR were protected with Cbz groups and their primary alcohols were capped with trityl and silyl moieties, respectively. The resulting intermediates retained 6 secondary hydroxyls, 4 of which, involved in trans -diols, were then subjected to deoxygenation to provide intermediates 43 and 45 .…”