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. 2023 Jan 3;18(1):e202200486.
doi: 10.1002/cmdc.202200486. Epub 2022 Oct 28.

Importance of Co-operative Hydrogen Bonding in the Apramycin-Ribosomal Decoding A-Site Interaction

Michael G Pirrone  1 , Chennaiah Ande  1 , Klara Haldimann  2 , Sven N Hobbie  2 , Andrea Vasella  3 , Erik C Böttger  2 , David Crich  4
Affiliations

Importance of Co-operative Hydrogen Bonding in the Apramycin-Ribosomal Decoding A-Site Interaction

Michael G Pirrone et al. ChemMedChem. .

Abstract

An intramolecular hydrogen bond between the protonated equatorial 7'-methylamino group of apramycin and the vicinal axial 6'-hydroxy group acidifies the 6'-hydroxy group leading to a strong hydrogen bond to A1408 in the ribosomal drug binding pocket in the decoding A site of the small ribosomal subunit. In 6'-epiapramycin, the trans-nature of the 6'-hydroxy group and the 7'-methylamino group results in a much weaker intramolecular hydrogen bond, and a consequently weaker cooperative hydrogen bonding network with A1408, resulting overall in reduced inhibition of protein synthesis and antibacterial activity.

Keywords: aminoglycoside modifying enzymes; aminoglycosides; antibacterial; antiribosomal activity; hydrogen bonding.

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Conflict of interest statement

S. N. H., A. V., E. C. B. and D. C. are founders of an equity holders in Juvabis AG, a biotech company developing aminoglycoside antibiotics

Figures

Figure 1
Figure 1
Structures of apramycin, paromomycin, neomycin, and gentamicin and the Types I (a) and II (b and c) pseudo‐base pair interactions.
Figure 2
Figure 2
Structures of 6’‐epiapramycin 5, bicyclic paromomycin analogs 6 and 7, and of aprosamine 8, and 6’‐epiaprosamine 9.
Figure 3
Figure 3
Target molecules 10 and 11.
Scheme 1
Scheme 1
Synthesis of the glycosyl acceptors 17 and 20 and the aprosamine alditols 21 and 22.
Scheme 2
Scheme 2
Synthesis of the epimeric 8’‐deoxyapralogs 10 and 11.
Scheme 3
Scheme 3
Preparation of the trans‐ and cis‐vicinal amino alcohols 28 and 31 and their butyrate salts 29 and 32.
Figure 4
Figure 4
Compounds screened for antiribosomal and antimicrobial activity.
Figure 5
Figure 5
Decoding A sites of prokaryotic and eukaryotic ribosomes. The bacterial AGA binding pocket is boxed and the A1408G substitution is colored green.
Figure 6
Figure 6
Pseudo‐base pair interactions; a) paromomycin (X=O) and neomycin (X=N+H2) with A1408; b) apramycin with A1408; c) paromomycin with 1408G; d) neomycin with 1408G with indicated steric clash; and e) apramycin with 1408G with indicated steric clash.
Figure 7
Figure 7
Concentration dependence of the ammonium resonance in protonated the trans‐ (gluco‐) and cis‐vicinal (allo‐) amino alcohols 29 and 32.
See this image and copyright information in PMC

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