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Structure-Activity Relationships for 5'' Modifications of 4,5-Aminoglycoside Antibiotics - PubMed

  • ️Sat Jan 01 2022

Structure-Activity Relationships for 5'' Modifications of 4,5-Aminoglycoside Antibiotics

Jonathan C K Quirke et al. ChemMedChem. 2022.

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.

Keywords: aminoglycoside modifying enzymes; antibacterial; antiribosomal; ototoxicity.

© 2022 Wiley-VCH GmbH.

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Conflict of interest statement

Conflict of Interest

AV, ECB, SNH, and DC are cofounders of and equity holders in Juvabis AG, a biotech start-up developing aminoglycoside antibiotics.

Figures

Figure 1.
Figure 1.

Structures of select 4,5- and 4,6-AGAs.

Figure 2.
Figure 2.

Some established neomycin 5”-derivatives.

Figure 3.
Figure 3.

Apralogs, advanced apralogs, and propylamycin derivatives.

Figure 4.
Figure 4.

Set of parent compounds and derivatives screened.

Figure 5.
Figure 5.

Decoding A sites of prokaryotic and eukaryotic ribosomes. The bacterial AGA binding pocket is boxed. The bacterial numbering scheme is illustrated for the AGA binding pocket. Changes from the bacterial ribosome binding pocket are colored green. The A1555G mutant conferring hypersusceptibility to AGA ototoxicity is colored red.

Figure 6.
Figure 6.

Structure of the Experimental Drug ELX-02.

Figure 7.
Figure 7.

Partial crystal structure of paromomycin bound to the decoding A site of Thermus thermophilus (PDB ID 1FJG), with dashed blue lines denoting hydrogen bonds.

Figure 8.
Figure 8.

a) Proposed hydrogen bonding scheme between N2’, N5”, and G1491, and the ring I A1408 pseudo-base pair in the 5”-deoxy-5”-amino of the 6’amino (X = NH2+) and 6’hydroxy AGAs (X = O), and b) Proposed hydrogen bonding scheme in the 5”-amino apralog interaction with the target.

Scheme 1.
Scheme 1.

Synthesis of 4”-des(hydroxymethyl)neomycin 27.

Scheme 2.
Scheme 2.

Synthesis of 5”-deoxy, 5”-deoxy-5”-amino, and 5”-deoxy-5”-amidoneomycin derivatives.

Scheme 3.
Scheme 3.

Synthesis of 4”-des(hydroxymethyl)paromomycin.

Scheme 4.
Scheme 4.

Synthesis of 5”-deoxy, 5”-deoxy-5”-amino, and 5”-deoxy-5”-amidoparomomycin derivatives.

Scheme 5.
Scheme 5.

Synthesis of 4”-des(hydroxymethyl)ribostamycin.

Scheme 6.
Scheme 6.

Synthesis of 5”-deoxy-5”-amino and 5”-deoxy-5”-amidoribostamycin derivatives.

Scheme 7.
Scheme 7.

Synthesis of apralog and advanced apralog derivatives.

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