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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Anti-Bacterial Agents / adverse effects
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Anti-Bacterial Agents / classification*
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Benzoates / chemistry
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Benzoates / pharmacology
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Benzoates / therapeutic use
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Benzoates / toxicity
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / microbiology
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Cell Death / drug effects
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Cell Line
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Drug Synergism
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Gentamicins / pharmacology
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Gentamicins / therapeutic use
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Humans
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Lipid Bilayers / chemistry
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Methicillin-Resistant Staphylococcus aureus / cytology
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Methicillin-Resistant Staphylococcus aureus / drug effects*
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Methicillin-Resistant Staphylococcus aureus / genetics
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Methicillin-Resistant Staphylococcus aureus / growth & development
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Mice
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Microbial Sensitivity Tests
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Molecular Dynamics Simulation
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Mutation
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Naphthols / chemistry
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Naphthols / pharmacology
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Naphthols / therapeutic use
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Naphthols / toxicity
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Retinoids / chemistry
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Retinoids / pharmacology*
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Retinoids / therapeutic use
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Retinoids / toxicity
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Staphylococcal Infections / drug therapy*
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Staphylococcal Infections / microbiology*
Substances
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4-(6-hydroxy-7-tricyclo(3.3.1.13,7)dec-1-yl-2-naphthalenyl)benzoic acid
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Anti-Bacterial Agents
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Benzoates
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CD 437
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Gentamicins
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Lipid Bilayers
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Naphthols
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Retinoids
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adarotene