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Author Notes:

E.M.: emylonakis@lifespan.org

Complete list of author contributions available in full text.

We thank the Institute of Chemistry and Cell Biology-Longwood at Harvard Medical School for providing the chemical libraries used in this study.

We thank L. Rice for providing the E. faecium strains; K. Bayles and J. Endres for providing plasmid pBK123; J. Saavedra for assistance with next-generation sequencing library preparation; and S. Khalid for providing the atomic structures and force fields of the phosphatidylglycerol, Lys-PG and DPG lipids.

The simulations reported were performed on resources provided by the Extreme Science and Engineering Discovery Environment through grant MSS090046; and the Center for Computation and Visualization at Brown University.

The authors declare competing interests: details are available in the online version of the paper.

Subjects:

Research Funding:

This study was supported by National Institutes of Health grant P01 AI083214 to M.S.G., F.M.A. and E.M.; by National Science Foundation grant CMMI-1562904 to H.G.; and by National Institute of General Medical Sciences grant 1R35GM119426; and National Science Foundation grant NSF1755698 to W.M.W.

D.VT is supported by National Eye Institute grant EY028222.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • STAPHYLOCOCCUS-AUREUS
  • IN-VITRO
  • RESISTANCE
  • CD437
  • ENDOCARDITIS
  • PEPTIDES
  • ST1926
  • SYSTEM
  • AGENTS
  • GRARS

A new class of synthetic retinoid antibiotics effective against bacterial persisters

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Journal Title:

Nature

Volume:

Volume 556, Number 7699

Publisher:

, Pages 103-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant € persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

Copyright information:

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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