Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens

Abstract

Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or ribosomal RNA methyl transferases.

Synthesis, ribosomal selectivity, and antibacterial activity of netilmicin 4′-derivatives

“…This pattern of reduced activity upon 4′-substitution corroborates our earlier observations on the functionalization of the 4′-hydroxy group in the kanamycin series of 4,6-AGAs, 3 but is in stark contrast to the 4,5-series of AGAs. 4 The reduced activity seen on modification of netilmicin at the 4′-position is accompanied by reduced target selectivity, again in contrast to the effects of comparable modifications in the 4,5-series of AGAs. 1,2,4 When combined with recent indications from resistome analysis that a much broader range of AMEs act on the 4,6-than the 4,5-series of AGAs, 20 these observations suggest that developmental programs for next generation AGAs should favour the 4,5over the 4,6-series.…”

“…This pattern of reduced activity and selectivity contrasts with that seen in the 4,5-series, where the introduction of the 4′-deoxy-4′-ethylthio and especially the 4′deoxy-4′-propyl modification have little effect on activity against the bacterial ribosome and result in increased selectivity (Table 1). 4 The pattern of reduced antibacterioribosomal activity on substitution at the 4′-position is, however, reminiscent of that seen in the kanamycin series of 4,6-AGAs and does not encourage further work in this direction. 3…”

“…3 More recently, we reported that replacement of the 4′-hydroxy group of paromomycin by an ethylthio group or by a propyl group, as in 4 or 5, resulted in marked increases in ribosomal selectivity, borne out by in vivo measurements in the guinea pig model, without the reduction in antibacterial activity attendant on formation of the ethers 2 and 3. 4 Thus prompted, we turned to the 4,6-DOS class of AGAs, and the installation of ethylthio and alkyl chains at the 4′-position of netilmicin 6, reputedly the least ototoxic of its class. [5][6][7][8][9][10] Accordingly, we re-port on the synthesis of a small series of 4′-derivatives of the 4,6-DOS AGA 6, and on their ribosomal selectivity and antibacterial activity against a set of representative Gram-negative and Gram-positive bacterial pathogens.…”

Functionally critical residues in the aminoglycoside resistance-associated methyltransferase RmtC play distinct roles in 30S substrate recognition

“…Additionally, progress in mitochondrial ribosome structural biology (24,25) and semi-synthesis of novel aminoglycosides (26,27) can support future efforts to design new aminoglycosides with fewer side effects. As such, this important class of antimicrobials has the potential to be exceptionally useful in the treatment of serious hospital-based infections, especially those caused by Gram negative pathogens.…”

The relationship between the structure and toxicity of aminoglycoside antibiotics

“…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 .…”