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; Christopher E Heise

doi:10.1038/s41586-018-0483-6

Optimized arylomycins are a new class of Gram-negative antibiotics

Nature. 2018 Sep;561(7722):189-194. doi: 10.1038/s41586-018-0483-6. Epub 2018 Sep 12.

Authors

Peter A Smith^#¹, Michael F T Koehler^#², Hany S Girgis³, Donghong Yan⁴, Yongsheng Chen⁵, Yuan Chen⁶, James J Crawford², Matthew R Durk⁶, Robert I Higuchi^{7

8}, Jing Kang⁴, Jeremy Murray⁹, Prasuna Paraselli^{7

10}, Summer Park⁴, Wilson Phung¹¹, John G Quinn¹², Tucker C Roberts^{7

13}, Lionel Rougé⁹, Jacob B Schwarz^{2

14}, Elizabeth Skippington¹⁵, John Wai⁵, Min Xu⁴, Zhiyong Yu⁵, Hua Zhang⁴, Man-Wah Tan³, Christopher E Heise^{16

17}

Affiliations

¹ Department of Infectious Diseases, Genentech, South San Francisco, CA, USA. [email protected].
² Department of Discovery Chemistry, Genentech, South San Francisco, CA, USA.
³ Department of Infectious Diseases, Genentech, South San Francisco, CA, USA.
⁴ Department of Translational Immunology, Genentech, South San Francisco, CA, USA.
⁵ Department of Chemistry, Wuxi AppTec, Shanghai, China.
⁶ Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA, USA.
⁷ RQx Pharmaceuticals, La Jolla, CA, USA.
⁸ Retrovirox, San Diego, CA, USA.
⁹ Department of Structural Biology, Genentech, South San Francisco, CA, USA.
¹⁰ Vertex, San Diego, CA, USA.
¹¹ Department of Microchem Proteomics, Genentech, South San Francisco, CA, USA.
¹² Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA.
¹³ Aduro Biotech, Berkeley, CA, USA.
¹⁴ FLX Bio, South San Francisco, CA, USA.
¹⁵ Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA, USA.
¹⁶ Department of Infectious Diseases, Genentech, South San Francisco, CA, USA. [email protected].
¹⁷ Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA. [email protected].

^# Contributed equally.

PMID: 30209367
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / classification*
Anti-Bacterial Agents / pharmacology*
Biocatalysis / drug effects
Biological Products / classification
Biological Products / pharmacology
Drug Resistance, Multiple, Bacterial / drug effects
Escherichia coli / enzymology
Gram-Negative Bacteria / drug effects*
Gram-Negative Bacteria / enzymology
Gram-Negative Bacteria / pathogenicity
Gram-Negative Bacterial Infections / drug therapy
Gram-Negative Bacterial Infections / microbiology
Klebsiella pneumoniae / drug effects
Klebsiella pneumoniae / enzymology
Klebsiella pneumoniae / pathogenicity
Lysine / metabolism
Membrane Proteins / antagonists & inhibitors
Microbial Sensitivity Tests
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Porins
Protein Binding
Protein Domains
Serine Endopeptidases
Substrate Specificity

Substances

Anti-Bacterial Agents
Biological Products
Membrane Proteins
Peptides, Cyclic
Porins
arylomycin A-C16
Serine Endopeptidases
type I signal peptidase
Lysine