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J Am Chem Soc. 2019 Mar 27;141(12):5051-5061. doi: 10.1021/jacs.9b01693. Epub 2019 Mar 13.

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.

Author information

1
Department of Chemistry , Wayne State University , 5101 Cass Avenue , Detroit , Michigan 48202 , United States.
2
Institut für Medizinische Mikrobiologie , Universität Zürich , 28 Gloriastrasse , 8006 Zürich , Switzerland.
3
Department of Biological Sciences , University of Illinois at Chicago , 900 South Ashland Avenue , Chicago , Illinois 60607 , United States.
4
Kresge Hearing Research Institute, Department of Otolaryngology , University of Michigan , 1150 West Medical Center Drive , Ann Arbor , Michigan 48109 , United States.
5
Department of Medicinal Chemistry and Pharmacognosy , University of Illinois at Chicago , 900 South Ashland Avenue , Chicago , Illinois 60607 , United States.
6
Laboratorium für Organische Chemie , ETH Zürich , Vladimir-Prelog-Weg 1-5/10 , 8093 Zürich , Switzerland.

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 ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.

PMID:
30793894
DOI:
10.1021/jacs.9b01693

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