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

Optimized arylomycins are a new class of Gram-negative antibiotics

Peter A Smith #  1 , Michael F T Koehler #  2 , Hany S Girgis  3 , Donghong Yan  4 , Yongsheng Chen  5 , Yuan Chen  6 , James J Crawford  2 , Matthew R Durk  6 , Robert I Higuchi  7   8 , Jing Kang  4 , Jeremy Murray  9 , Prasuna Paraselli  7   10 , Summer Park  4 , Wilson Phung  11 , John G Quinn  12 , Tucker C Roberts  7   13 , Lionel Rougé  9 , Jacob B Schwarz  2   14 , Elizabeth Skippington  15 , John Wai  5 , Min Xu  4 , Zhiyong Yu  5 , Hua Zhang  4 , Man-Wah Tan  3 , Christopher E Heise  16   17
Affiliations

Optimized arylomycins are a new class of Gram-negative antibiotics

Peter A Smith et al. Nature. 2018 Sep.

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.

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References

    1. Ventola, C. L. The antibiotic resistance crisis part 1: causes and threats. P&T 40, 277–283 (2015).
    1. Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 197, 1079–1081 (2008).
    1. Schimana, J. et al. Arylomycins A and B, new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tü 6075. I. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. (Tokyo) 55, 565–570 (2002).
    1. Kulanthaivel, P. et al. Novel lipoglycopeptides as inhibitors of bacterial signal peptidase I. J. Biol. Chem. 279, 36250–36258 (2004).
    1. Smith, P. A., Powers, M. E., Roberts, T. C. & Romesberg, F. E. In vitro activities of arylomycin natural-product antibiotics against Staphylococcus epidermidis and other coagulase-negative staphylococci. Antimicrob. Agents Chemother. 55, 1130–1134 (2011).

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