Optimized Arylomycins Are a New Class of Gram-Negative Antibiotics. Smith, P. A., Koehler, M. F. T., Girgis, H. S., Yan, D., Chen, Y., Chen, Y., Crawford, J. J., Durk, M. R., Higuchi, R. I., Kang, J., Murray, J., Paraselli, P., Park, S., Phung, W., Quinn, J. G., Roberts, T. C., Rougé, L., Schwarz, J. B., Skippington, E., Wai, J., Xu, M., Yu, Z., Zhang, H., Tan, M., & Heise, C. E. Nature, 561(7722):189–194, September, 2018.
doi  abstract   bibtex   
Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins – a class of natural products with weak activity and limited spectrum – to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.
@article{smithOptimizedArylomycinsAre2018,
  title = {Optimized Arylomycins Are a New Class of {{Gram}}-Negative Antibiotics},
  author = {Smith, Peter A. and Koehler, Michael F. T. and Girgis, Hany S. and Yan, Donghong and Chen, Yongsheng and Chen, Yuan and Crawford, James J. and Durk, Matthew R. and Higuchi, Robert I. and Kang, Jing and Murray, Jeremy and Paraselli, Prasuna and Park, Summer and Phung, Wilson and Quinn, John G. and Roberts, Tucker C. and Roug{\'e}, Lionel and Schwarz, Jacob B. and Skippington, Elizabeth and Wai, John and Xu, Min and Yu, Zhiyong and Zhang, Hua and Tan, Man-Wah and Heise, Christopher E.},
  year = {2018},
  month = sep,
  volume = {561},
  pages = {189--194},
  issn = {0028-0836},
  doi = {10.1038/s41586-018-0483-6},
  abstract = {Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins -- a class of natural products with weak activity and limited spectrum -- to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.},
  journal = {Nature},
  keywords = {*imported-from-citeulike-INRMM,~INRMM-MiD:c-14635569,~to-add-doi-URL,anthropic-feedback,antibiotics,bacteria,bacterial-diseases,connectivity,emergency-management,human-health},
  lccn = {INRMM-MiD:c-14635569},
  number = {7722}
}
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