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

Journal of the American Chemical Society
Takahiko MatsushitaDavid Crich

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 rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative...Continue Reading

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Citations

Dec 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mary E O'SullivanAnthony J Ricci
May 4, 2020·Bioorganic & Medicinal Chemistry Letters·Moriah Jospe-KaufmanMicha Fridman
Dec 20, 2019·ACS Infectious Diseases·Erik C Böttger, David Crich
Apr 29, 2020·Organic Letters·Parasuraman Rajasekaran, David Crich
Jan 22, 2020·Journal of the American Chemical Society·Sivan Louzoun ZadaMicha Fridman

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