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Nature. 2018 Apr 5;556(7699):103-107. doi: 10.1038/nature26157. Epub 2018 Mar 28.

A new class of synthetic retinoid antibiotics effective against bacterial persisters.

Author information

1
Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
2
School of Engineering, Brown University, Providence, Rhode Island 02903, USA.
3
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.
4
Department of Microbiology and Immunobiology, Harvard Medical School, Massachusetts 02115, USA.
5
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
6
Emory Antibiotic Resistance Center, Emory University, Atlanta, Georgia 30322, USA.
7
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
8
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
9
Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois 60208, USA.

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.

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PMID:
29590091
DOI:
10.1038/nature26157
[Indexed for MEDLINE]

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