Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens.
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.
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.
David C
DC
McKinney
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.
Gregory S
GS
Basarab
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.
Alexis I
AI
Cocozaki
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.
Melinda A
MA
Foulk
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.
Matthew D
MD
Miller
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.
Anatoly M
AM
Ruvinsky
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.
Clay W
CW
Scott
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.
Kumar
K
Thakur
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.
Liang
L
Zhao
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.
Ed T
ET
Buurman
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.
Sridhar
S
Narayan
Antibacterial; Gram-negative; natural product; negamycin; ribosome