Influence of 4′-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

Abstract

A series of 20 4'-O-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the d-pentopyranosides than for the l-pentopyranosides and d-hexopyranosides. In particular, 4'-O-β-d-xylopyranosyl paromomycin shows antibacterioribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome associated with hypersusceptibility to drug-induced ototoxicity. Compound antibacterioribosomal activity correlates with antibacterial activity, and the ribosomally more active compounds show activity against Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). The paromomycin glycosides retain activity against clinical strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4'-O-glycosylation blocking the action of 4'-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.

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

“…Consistent with the precedent in the paromomycin and other series, 31,32,38,76 derivatization of the 4′-hydroxy group as in 11 and 37 overcomes resistance due to the presence of the aminoglycoside nucleotidyltranferase ANT(4′,4″) (Table 4). Consistent with the lack of susceptibility of the parent, and the general lower susceptibility of the 4,5-AGAs than the 4,6-AGAs to AACs, 35 none of the derivatives screened were significantly inactivated by the presence of either the AAC(3) or AAC(2′) resistance determinants.…”

“…31,32 In particular we determined that functionalization at the paromomycin 4′-position with short alkyl chains, as in the 4′- O -ethyl derivative 5 (Figure 1), increases selectivity for the prokaryotic over the eukaryotic ribosomes, decreases oto- and nephrotoxicity, and overcomes several AME′s that act on the parent. 31 In addition, like apramycin, these 4,5-AGA derivatives are little susceptible to inactivation by the 1405G ribosomal methyltransferases, which completely abrogate the activity of all 4,6-AGAs, including plazomicin.…”

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

“…The A1555G mutant conferring hypersusceptibility to AGA ototoxicity is coloured red. Reproduced from ref 43. Copyright 2015 American Chemical Society…”

“…Animal models confirm the expected significantly reduced ototoxicity of selected paromomycin derivatives. 41–42 However, except for certain 4′- O -glycosyl derivatives, 43 this was accompanied by reduced antibacterial activity.…”

Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells

“…In addition, there are multiple enzymes that work on aminoglycosides to inactivate their antibiotic activity, which limits their use in the clinic [5]. A large variety of structural analogues, including amphiphilic aminoglycosides [6], conformationally-locked aminoglycosides, and glycosylated aminoglycosides [7,8] have been synthesized to overcome the adverse effects [3]. These efforts led to the discovery of derivatives that cannot be modified by aminoglycoside-inactivating enzymes [9,10], that have reduced toxicity [6], and even inhibit bacterial growth via new mechanisms of action [11,12].…”