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Macrolide transport in Escherichia coli strains having normal and altered OmpC and/or OmpF porins

J O Capobianco1, R C Goldman

  • 1Anti-infective Research Division, Department 47 M, Building AP9A, Abbott Laboratories, One Abbott Park Road, Abbott Park, IL 60064-3500, USA.

International Journal of Antimicrobial Agents
|August 1, 1994
PubMed

Insights

Escherichia coli porin mutations significantly increased macrolide antibiotic uptake and decreased minimum inhibitory concentrations (MICs). This suggests porins are key entry channels for hydrophilic antibiotics like erythromycin and azithromycin.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Pharmacology

Background:

  • Outer membrane porins (OMPs) in Gram-negative bacteria like Escherichia coli regulate the passage of small molecules.
  • Macrolide antibiotics, such as erythromycin and azithromycin, are important antimicrobial agents whose transport across the bacterial outer membrane is not fully understood.
  • Porin channels are potential entry routes for hydrophilic drugs, influencing their efficacy.

Purpose of the Study:

  • To investigate the role of OmpC and OmpF porins in Escherichia coli on the uptake of erythromycin and azithromycin.
  • To determine the impact of porin alterations on macrolide minimum inhibitory concentrations (MICs).
  • To elucidate the mechanism of macrolide entry into Escherichia coli.

Main Methods:

  • Utilized radiolabeled [(14)C]erythromycin and [(14)C]azithromycin to quantify macrolide uptake rates.
  • Constructed and employed various Escherichia coli strains with mutations (insertions, deletions) in ompC and ompF genes, affecting OmpC and OmpF porin expression.
  • Measured minimum inhibitory concentrations (MICs) of macrolides against parent and mutant strains.
  • Assessed outer membrane permeability using 1-N-phenylnaphthylamine and evaluated drug entry mechanisms with polymyxin B.

Main Results:

  • Porin mutants exhibited a 2- to 1224-fold increase in macrolide transport compared to the wild-type strain.
  • A concurrent decrease in macrolide MICs was observed, ranging from 3- to 530-fold.
  • Enhanced permeability to hydrophobic molecules was noted in strains with altered porins, and macrolides did not displace polymyxin, ruling out self-promoted uptake.
  • High protonation and hydrophilic nature of macrolides at neutral pH support porin-mediated entry.

Conclusions:

  • Alterations in OmpC and OmpF porins significantly enhance the uptake of hydrophilic macrolide antibiotics into Escherichia coli.
  • Porin channels are the primary route for macrolide entry into the bacterial cell.
  • Modulating porin expression or function could be a strategy to overcome macrolide resistance.

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