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Retargeting Gram-Positive-Only Adarotene-Derived Antibacterials to Broad-Spectrum Antibiotics.

Salvatore Princiotto1, Luigi Cutarella2, Alessandra Fortuna3

  • 1Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, via Celoria 2, 20133 Milan, Italy.

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Researchers developed adarotene derivatives, like SPL207, to combat antibiotic resistance. SPL207 disrupts bacterial membranes, showing potential against Gram-negative pathogens and synergistic effects with colistin in resistant strains.

Keywords:
Gram-negativeGram-positiveadaroteneantibacterialbroad-spectrummultidrug-resistanceouter membrane

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Area of Science:

  • Medicinal Chemistry
  • Antimicrobial Drug Discovery
  • Molecular Pharmacology

Background:

  • Rising global antibiotic resistance poses a significant public health threat.
  • Gram-positive-only (GPO) antibiotics have limited efficacy against Gram-negative bacteria due to outer membrane penetration issues.
  • The World Health Organization (WHO) has identified priority pathogens requiring novel treatment strategies.

Purpose of the Study:

  • To design and synthesize novel adarotene derivatives to overcome Gram-negative outer membrane barriers.
  • To evaluate the antimicrobial activity and membrane-disrupting capabilities of these new compounds.
  • To explore potential synergistic effects with existing antibiotics against resistant strains.

Main Methods:

  • Synthesis of adarotene-derived compounds with positively charged groups.
  • Determination of minimum inhibitory concentrations (MICs) against Gram-positive and Gram-negative bacteria.
  • Fluorescence assays and confocal microscopy to assess membrane permeability disruption.
  • Molecular dynamics (MD) simulations to elucidate the mechanism of membrane interaction.

Main Results:

  • The derivative SPL207 exhibited MIC values between 8-64 µM against tested bacteria.
  • SPL207 effectively disrupted both outer and inner membrane integrity in Gram-negative bacteria.
  • Significant synergy was observed when SPL207 was combined with colistin against colistin-resistant *P. aeruginosa* strains.
  • MD simulations revealed SPL207 acts as a membrane destabilizer, enhancing ion diffusion and lipid destabilization.

Conclusions:

  • Adarotene derivatives show promise as a new class of antimicrobial agents targeting membrane integrity.
  • SPL207 demonstrates a proof of concept for overcoming Gram-negative outer membrane challenges.
  • Further structural optimization is needed to achieve clinically relevant MIC values against multidrug-resistant (MDR) pathogens.