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Laboratory Techniques Used to Maintain and Differentiate Biotypes of Vibrio cholerae Clinical and Environmental Isolates
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The Vibrio cholerae CBASS phage defence system modulates resistance and killing by antifolate antibiotics

Susanne Brenzinger1, Martina Airoldi1,2, Adewale Joseph Ogunleye1

  • 1Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany.

Nature Microbiology
|January 3, 2024
PubMed

Insights

Vibrio cholerae's toxic CBASS system enhances antifolate antibiotic sensitivity, turning bacteriostatic drugs into bactericidal agents. This interaction, dependent on folate binding, offers new antimicrobial strategies.

Area of Science:

  • Microbiology and Molecular Biology
  • Antimicrobial Drug Discovery
  • Bacterial Toxin Systems

Background:

  • Toxin-antitoxin systems are toxic bacterial modules with antimicrobial potential, but clinical applications are limited.
  • Cyclic-oligonucleotide-based anti-phage signaling systems (CBASS) represent another class of toxic bacterial modules.
  • Antifolate antibiotics are traditionally bacteriostatic, inhibiting bacterial growth rather than causing cell death.

Purpose of the Study:

  • To investigate the interaction between the Vibrio cholerae CBASS system and antifolate antibiotics.
  • To determine if CBASS activation can enhance the efficacy of bacteriostatic antibiotics.
  • To elucidate the mechanism underlying the CBASS-antifolate interaction and its implications for antimicrobial therapy.

Main Methods:

  • Assessed the effect of CBASS activation on bacterial sensitivity to antifolate antibiotics in Vibrio cholerae.
  • Measured cyclic-oligonucleotide production by DncV upon treatment with antifolates to confirm CBASS activation.
  • Investigated the specificity of the interaction by examining related nucleotidyltransferases and folate-binding pockets.
  • Analyzed the impact of antifolate resistance genes on the CBASS-antifolate interaction.

Main Results:

  • CBASS activation increased Vibrio cholerae sensitivity to antifolate antibiotics by up to 10-fold.
  • Antifolate treatment led to cyclic-oligonucleotide production by DncV, indicating CBASS activation.
  • The interaction is specific to CBASS systems with similar folate-binding pockets, suggesting antifolates release DncV inhibition.
  • Antifolate resistance genes abolished the interaction, highlighting potential coevolution with CBASS.

Conclusions:

  • Toxic bacterial modules like CBASS can significantly impact antibiotic activity.
  • CBASS confers bactericidal activity to classical bacteriostatic antifolate antibiotics.
  • This study reveals a novel mechanism for enhancing antibiotic efficacy and offers potential for new antimicrobial strategies.

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