Title: 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. In this work, 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 inmore » 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.« less

Authors:

Matsushita, Takahiko ^[1]; Sati, Girish C. ^[1]; Kondasinghe, Nuwan ^[1]; Pirrone, Michael G. ^[1]; Kato, Takayuki ^[1]; Waduge, Prabuddha ^[1]; Kumar, Harshitha Santhosh ^[2]; Sanchon, Adrian Cortes ^[2]; Dobosz-Bartoszek, Malgorzata ^[3]; Shcherbakov, Dimitri ^[2]; Juhas, Mario ^[2]; Hobbie, Sven N. ^[2]; Schrepfer, Thomas ^[4]; Chow, Christine S. ^[1]; Polikanov, Yury S. ^[3]; Schacht, Jochen ^[4]; Vasella, Andrea ^[5]; Böttger, Erik C. ^[2]; Crich, David  ^[1]

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+ Show Author Affiliations

1. Wayne State Univ., Detroit, MI (United States)
2. Univ. Zürich (Switzerland)
3. Univ. of Illinois, Chicago, IL (United States)
4. Univ. of Michigan, Ann Arbor, MI (United States)
5. ETH Zürich (Switzerland)

Publication Date:

Fri Feb 22 00:00:00 EST 2019

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:

National Institutes of Health (NIH); Swiss National Science Foundation (SNF); Illinois State; National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC)

OSTI Identifier:

1513026

Grant/Contract Number:  

P41 GM103403; S10-RR029205; S10-OD021527; AC02-06CH11357

Resource Type:

Accepted Manuscript

Journal Name:

Journal of the American Chemical Society

Additional Journal Information:

Journal Volume: 141; Journal Issue: 12; Journal ID: ISSN 0002-7863

Publisher:

American Chemical Society (ACS)

Country of Publication:

United States

Language:

ENGLISH

Subject:

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Redox reactions; Modification; Antibacterial activity; Reaction products; Selectivity