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A new class of synthetic retinoid antibiotics effective against bacterial persisters

Wooseong Kim1, Wenpeng Zhu2, Gabriel Lambert Hendricks1

  • 1Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.

Nature
|March 29, 2018
PubMed

Insights

New synthetic retinoids, CD437 and CD1530, effectively kill growing and dormant methicillin-resistant Staphylococcus aureus (MRSA) cells. These compounds show promise as novel antimicrobials against persistent bacterial infections.

Area of Science:

  • Microbiology
  • Drug Discovery
  • Molecular Biology

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant treatment challenge due to antibiotic tolerance in dormant persister cells.
  • Conventional antibiotics are ineffective against these persister cells, necessitating the development of novel antibacterial agents.

Purpose of the Study:

  • To identify novel therapeutics effective against both growing and persister MRSA cells.
  • To explore the potential of synthetic retinoids as a new class of antimicrobials.

Main Methods:

  • Utilized a Caenorhabditis elegans-MRSA infection screen to identify potential drug candidates.
  • Employed all-atom molecular dynamics simulations to understand the mechanism of action.
  • Evaluated drug efficacy in a mouse model of chronic MRSA infection.

Main Results:

  • Identified two synthetic retinoids, CD437 and CD1530, that kill both growing and persister MRSA by disrupting lipid bilayers.
  • Demonstrated synergism with gentamicin and a low probability of resistance selection for these retinoids.
  • An optimized analogue of CD437 showed retained anti-persister activity with improved cytotoxicity and efficacy in a mouse model.

Conclusions:

  • Synthetic retinoids, such as CD437 and CD1530, represent a promising new class of antimicrobials against difficult-to-treat Gram-positive bacterial infections.
  • These compounds effectively target both growing and dormant MRSA, offering a potential solution for chronic and recurrent infections.
  • Further development of synthetic retinoids could lead to novel treatments for persistent bacterial infections.

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