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Updated: Jun 13, 2025

Anti-virulent Disruption of Pathogenic Biofilms using Engineered Quorum-quenching Lactonases
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An Engineered Prodrug Selectively Suppresses β-Lactam-Resistant Bacteria in a Mixed Microbial Setting.

Addison M Duda1, Helena R Ma2, César A Villalobos2

  • 1Department of Chemistry, Duke University, Durham, North Carolina 27708, United States.

ACS Infectious Diseases
|June 12, 2025
PubMed
Summary

New prodrug AcephPT targets bacteria with extended-spectrum beta-lactamases (ESBLs). This strategy selectively suppresses resistant strains, offering a novel approach to combatting antibiotic resistance and promoting antimicrobial stewardship.

Keywords:
antibiotic resistanceantimicrobial stewardshipextended-spectrum-β-lactamasepolymicrobialprodrugβ-lactam

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Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Antimicrobial Resistance

Background:

  • The increasing prevalence of antibiotic resistance, particularly β-lactam resistance, poses a significant threat to public health.
  • Extended-spectrum β-lactamases (ESBLs) are key enzymes conferring resistance to many β-lactam antibiotics in Gram-negative bacteria.

Purpose of the Study:

  • To engineer a novel β-lactam prodrug, AcephPT, designed for selective activation by ESBLs.
  • To demonstrate the selective suppression of ESBL-producing bacteria by AcephPT, while sparing susceptible bacteria.

Main Methods:

  • Design and synthesis of the β-lactam prodrug AcephPT.
  • Testing AcephPT activity in clonal populations and mixed microbial cultures containing both ESBL-producing and non-producing bacteria.
  • Utilizing time-course Nuclear Magnetic Resonance (NMR) spectroscopy to confirm prodrug activation.

Main Results:

  • AcephPT demonstrated selective suppression of Gram-negative bacteria producing ESBLs.
  • Effective selectivity was observed for both laboratory strains and clinical isolates expressing ESBLs.
  • NMR experiments confirmed hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria.

Conclusions:

  • AcephPT selectively targets and suppresses ESBL-producing bacteria.
  • This approach offers a potential strategy to combat β-lactam resistance while preserving the efficacy of antibiotics and supporting antimicrobial stewardship.