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Global distribution of α/β hydrolase family macrolide esterases in Gram-positive bacteria

Yang Zhou1, Yongqiang Yang2, Yuqi Mao1

  • 1Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of pharmacy, Chengdu University, Chengdu, Sichuan 610106, China.

The ISME Journal
|November 26, 2025
PubMed

Insights

Macrolide esterases (MLEs), previously unknown in Gram-positive bacteria, confer significant macrolide resistance. Their ancient origin and global spread highlight a critical, underrecognized threat to antibiotic effectiveness.

Area of Science:

  • Microbiology
  • Genomics
  • Antimicrobial Resistance

Background:

  • Macrolide antibiotics are crucial for treating infections but face diminishing effectiveness due to rising antimicrobial resistance.
  • Macrolide esterases (MLEs) are primary mechanisms of macrolide resistance, previously identified only in Gram-negative bacteria.
  • The absence of MLEs in Gram-positive bacteria represented a knowledge gap in understanding macrolide resistance mechanisms.

Purpose of the Study:

  • To investigate the presence and function of macrolide esterases (MLEs) in Gram-positive bacteria.
  • To determine the evolutionary origin and global distribution of Gram-positive MLEs.
  • To assess the impact of Gram-positive MLEs on macrolide resistance and inform One Health strategies.

Main Methods:

  • Bioinformatic mining of over 500,000 Gram-positive bacterial genomes to identify candidate MLE proteins.
  • Functional validation of six representative MLEs through resistance assays in model organisms (Escherichia coli and Bacillus subtilis).
  • Phylogenetic analysis for temporal origin determination and global genomic surveys for distribution assessment.

Main Results:

  • Identification of 8707 candidate MLE proteins in Gram-positive bacteria.
  • Functional validation confirmed resistance to 16-membered macrolides, with Minimum Inhibitory Concentrations (MICs) increasing up to 128-fold.
  • Two validated MLEs demonstrated broad-spectrum activity against clinically relevant 16-membered macrolides.
  • Temporal analysis indicated Gram-positive MLEs originated at least 2.7 million years ago.
  • Genomic surveys revealed global distribution across 97 countries in diverse environments (clinical, food, agriculture, natural).

Conclusions:

  • Gram-positive bacteria harbor functional macrolide esterases, representing a significant and previously unrecognized mechanism of macrolide resistance.
  • The ancient origin and widespread distribution of these enzymes pose a substantial global health risk, necessitating urgent monitoring and mitigation strategies.
  • A One Health approach is essential to address the interconnected spread of macrolide resistance mediated by Gram-positive MLEs across human, animal, and environmental sectors.
Keywords:
antibiotic resistancegram-positive bacteriamacrolide esterases

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