Apralogs: Apramycin 5-O-Glycosides and Ethers with Improved Antibacterial Activity and Ribosomal Selectivity and Reduced Susceptibility to the Aminoacyltransferase (3)-IV Resistance Determinant

Abstract

Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a mono-substituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment

Two Cryptic Self‐Resistance Mechanisms in Streptomyces tenebrarius Reveal Insights into the Biosynthesis of Apramycin

“…Forschungsartikel biological properties than apramycin, [35] which is consistent with our notion that C-5 is critical for apramycinsa ctivity. Therefore,our study has important implications for the future development of next-generation AGAdrugs.…”

An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram‐negative Pathogens and Reduced ex vivo Cochleotoxicity

“…For the synthesis of 4 , a donor 7 was prepared in a simple two‐pot sequence via 6 from the known ribose derivative 5 , [15] and coupled under robust Helferich conditions to the apramycin derivative 8 followed by a one pot deprotection sequence involving saponification and Staudinger reduction of the azido groups (Scheme 1). As 8 is available in four steps from apramycin, [10b] the synthesis of 4 requires only six steps from the parent aminoglycoside 1 .…”

The relationship between the structure and toxicity of aminoglycoside antibiotics

“…Another study by the same group of a series of 5-O-(D-ribofuranosyl) apramycin derivatives indicated that certain modifications enhance selectivity for bacterial ribosomes. 13 For example, derivative 1 (Fig. 3), with an ethylene diamine modification at the C-5 position of the ribofuranose, was a more effective inhibitor of bacterial ribosome-mediated translation than apramycin without an undesired increase in inhibition of translation mediated by the hybrid ribosomes with eukaryotic Asites.…”

“…9 To date, multiple AGs have been isolated and thousands of semi-synthetic derivatives have been synthesized in an attempt to improve their pharmacological properties and to reveal structure-activity relationship. [10][11][12][13][14][15][16] Only a handful of natural and semisynthetic AGs are currently in clinical use, however. These include neomycin, tobramycin, gentamicin, and the semisynthetic derivative of the natural AG kanamycin A known as amikacin 17 .…”

“…3), had lower selectivity for bacterial relative to the mitochondrial hybrid ribosome but higher selectivity for the bacterial compared to the cytosolic hybrid ribosome than the parent. 13 This derivative was further tested in a mouse model of infection with E. coli and displayed a significantly better clearance of the infection than apramycin.…”