Optimized arylomycins are a new class of Gram-negative antibiotics
| Autor: | Yuan Chen, Matthew R. Durk, Lionel Rouge, Peter A. S. Smith, Man-Wah Tan, John S. Wai, Jacob Schwarz, Tucker C. Roberts, Jing Kang, Donghong Yan, Hany S. Girgis, Summer Park, John G. Quinn, Min Xu, Prasuna Paraselli, Christopher E. Heise, Jeremy Murray, Wilson Phung, Yongsheng Chen, James J. Crawford, Robert I. Higuchi, Zhiyong Yu, Michael F. T. Koehler, Elizabeth Skippington, Hua Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.drug_class Antibiotics Porins Microbial Sensitivity Tests Drug resistance Biology Peptides Cyclic 01 natural sciences Substrate Specificity Microbiology 03 medical and health sciences Antibiotic resistance Protein Domains In vivo Drug Resistance Multiple Bacterial Gram-Negative Bacteria Escherichia coli medicine Biological Products Signal peptidase Multidisciplinary 010405 organic chemistry Lysine Serine Endopeptidases Membrane Proteins biology.organism_classification Anti-Bacterial Agents 0104 chemical sciences Klebsiella pneumoniae 030104 developmental biology Type I signal peptidase Biocatalysis Molecular mechanism Gram-Negative Bacterial Infections Bacteria Protein Binding |
| Zdroj: | Nature. 561:189-194 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-018-0483-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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