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.
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The sequence reported in this paper has been deposited in the GenBank database, www.ncbi.nlm.nih.gov/genbank (accession numbers CP022611–CP022613). G0775, G3031, G8126 and G6850 are unique molecules proprietary to Genentech that are readily available on request. The authors declare that all other data supporting the findings of this study are available from the authors and/or included with the manuscript as Source Data (efficacy studies) or as Supplementary Information.
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We thank Confluence Discovery Technologies for running the enzymatic inactivation studies and WuXi Shanghai for determining MIC values to support the chemistry effort. We thank C. Peng, H. La, J. Z. Chen, F. Ma, X. Liang, S. Ubhayakar and the protein expression group from Genentech for supporting the research efforts required to discover G0775, J. Guillory for performing the whole-genome sequencing on CDC 0106, and B. Sellers for performing property calculations on synthesized compounds.
Nature thanks E. Brown, P. Hergenrother, T. Maier and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Journal of Industrial Microbiology & Biotechnology (2018)