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McKinney DC, Basarab GS, Cocozaki AI, et al. Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens. ACS Med Chem Lett. 2015;6(8):930-5doi: 10.1021/acsmedchemlett.5b00205.
McKinney, D. C., Basarab, G. S., Cocozaki, A. I., Foulk, M. A., Miller, M. D., Ruvinsky, A. M., Scott, C. W., Thakur, K., Zhao, L., Buurman, E. T., & Narayan, S. (2015). Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens. ACS medicinal chemistry letters, 6(8), 930-5. https://doi.org/10.1021/acsmedchemlett.5b00205
McKinney, David C, et al. "Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens." ACS medicinal chemistry letters vol. 6,8 (2015): 930-5. doi: https://doi.org/10.1021/acsmedchemlett.5b00205
McKinney DC, Basarab GS, Cocozaki AI, Foulk MA, Miller MD, Ruvinsky AM, Scott CW, Thakur K, Zhao L, Buurman ET, Narayan S. Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens. ACS Med Chem Lett. 2015 Jul 12;6(8):930-5. doi: 10.1021/acsmedchemlett.5b00205. eCollection 2015 Aug 13. PMID: 26288696; PMCID: PMC4538447.
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ACS Med Chem Lett. 2015 Jul 12;6(8):930-5. doi: 10.1021/acsmedchemlett.5b00205. eCollection 2015 Aug 13.

Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens.

ACS medicinal chemistry letters

David C McKinney, Gregory S Basarab, Alexis I Cocozaki, Melinda A Foulk, Matthew D Miller, Anatoly M Ruvinsky, Clay W Scott, Kumar Thakur, Liang Zhao, Ed T Buurman, Sridhar Narayan

Affiliations

  1. Departments of Chemistry and Bioscience, Infection Innovative Medicines; Structure and Biophysics, Discovery Sciences; Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.

PMID: 26288696 PMCID: PMC4538447 DOI: 10.1021/acsmedchemlett.5b00205

Abstract

Negamycin is a natural product with antibacterial activity against a broad range of Gram-negative pathogens. Recent revelation of its ribosomal binding site and mode of inhibition has reinvigorated efforts to identify improved analogues with clinical potential. Translation-inhibitory potency and antimicrobial activity upon modification of different moieties of negamycin were in line with its observed ribosomal binding conformation, reaffirming stringent structural requirements for activity. However, substitutions on the N6 amine were tolerated and led to N6-(3-aminopropyl)-negamycin (31f), an analogue showing 4-fold improvement in antibacterial activity against key bacterial pathogens. This represents the most potent negamycin derivative to date and may be a stepping stone toward clinical development of this novel antibacterial class.

Keywords: Antibacterial; Gram-negative; natural product; negamycin; ribosome

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