Optimized arylomycins are a new class of Gram-negative antibiotics

Peter A. Smith (), Michael F. T. Koehler, Hany S. Girgis, Donghong Yan, Yongsheng Chen, Yuan Chen, James J. Crawford, Matthew R. Durk, Robert I. Higuchi, Jing Kang, Jeremy Murray, Prasuna Paraselli, Summer Park, Wilson Phung, John G. Quinn, Tucker C. Roberts, Lionel Rougé, Jacob B. Schwarz, Elizabeth Skippington, John Wai, Min Xu, Zhiyong Yu, Hua Zhang, Man-Wah Tan and Christopher E. Heise ()
Additional contact information
Peter A. Smith: Genentech
Michael F. T. Koehler: Genentech
Hany S. Girgis: Genentech
Donghong Yan: Genentech
Yongsheng Chen: Wuxi AppTec
Yuan Chen: Genentech
James J. Crawford: Genentech
Matthew R. Durk: Genentech
Robert I. Higuchi: RQx Pharmaceuticals
Jing Kang: Genentech
Jeremy Murray: Genentech
Prasuna Paraselli: RQx Pharmaceuticals
Summer Park: Genentech
Wilson Phung: Genentech
John G. Quinn: Genentech
Tucker C. Roberts: RQx Pharmaceuticals
Lionel Rougé: Genentech
Jacob B. Schwarz: Genentech
Elizabeth Skippington: Genentech
John Wai: Wuxi AppTec
Min Xu: Genentech
Zhiyong Yu: Wuxi AppTec
Hua Zhang: Genentech
Man-Wah Tan: Genentech
Christopher E. Heise: Genentech

Nature, 2018, vol. 561, issue 7722, 189-194

Abstract: 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.

Keywords: Gram-negative Antibiotics; Signal Peptidase; Outer Membrane Penetration; Minimum Inhibitory Concentrations Measurement (MIC); ESKAPE Pathogens (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0483-6

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