A new class of synthetic retinoid antibiotics effective against bacterial persisters
By Wooseong Kim, Wenpeng Zhu, G. Hendricks, D. V. Tyne, Andrew D. Steele, Colleen E. Keohane, N. Fricke, Annie L. Conery, Steven Shen, Wen Pan and 9 more. Nature, 2018
356 citations recorded by the source corpus.
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.
Subfields: Infectious Diseases, Molecular Medicine, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/51cbf12e023727ca38818caf568d1eda37a24a4d
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Citations in the corpus
- Antimicrobial Resistance in ESKAPE Pathogens (2020, background): “Ebselen, a synthetic anti-inflammatory drug, and the oncology drugs adarotene and floxuridine have displayed bactericidal activity against MRSA and VRSA strains in vivo (448, 449).”
- Antibiotic resistance and persistence—Implications for human health and treatment perspectives (2020, unknown): “…437 and CD 1530 ). ª 2020 The Authors EMBO reports 21 : e 51034 | 2020 combination with gentamicin exhibited high efficacy in a murine thigh infection model highlighting the potential of retinoid derivatives as a new class of antibiotics and antipersister drugs (Kim et al , 2018; Kim et al , 2019).”