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Published on: July 7, 2020
The contribution of porins to enterobacterial drug resistance
Anne Davin-Regli1, Jean-Marie Pagès1, Julia Vergalli1
1Aix-Marseille Univ, INSERM, SSA, MCT, Marseille, France.
Abstract:
In Enterobacteriaceae, susceptibility to cephalosporins and carbapenems is often associated with membrane and enzymatic barrier resistance. For about 20 years, a large number of Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae presenting ß-lactam resistance have been isolated from medical clinics. In addition, some of the resistant isolates exhibited alterations in the outer membrane porin OmpC-OmpF orthologues, resulting in the complete absence of gene expression, replacement by another porin or mutations affecting channel properties. Interestingly, for mutations reported in OmpC-OmpF orthologues, major changes in pore function were found to be present in the gene encoding for OmpC. The alterations were located in the constriction region of the porin and the resulting amino acid substitutions were found to induce severe restriction of the lumen diameter and/or alteration of the electrostatic field that governs the diffusion of charged molecules. This functional adaptation through porins maintains the entry of solutes necessary for bacterial growth but critically controls the influx of harmful molecules such as β-lactams at a reduced cost. The data recently published show the importance of understanding the underlying parameters affecting the uptake of antibiotics by infectious bacteria. Furthermore, the development of reliable methods to measure the concentration of antibiotics within bacterial cells is key to combat impermeability-resistance mechanisms.
Insights
Bacterial resistance to cephalosporins and carbapenems in Klebsiella pneumoniae and Escherichia coli is linked to outer membrane porin OmpC alterations. These mutations restrict antibiotic entry, impacting treatment strategies for infectious diseases.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Resistance
Background:
- Enterobacteriaceae, including Klebsiella pneumoniae and Escherichia coli, commonly exhibit resistance to cephalosporins and carbapenems.
- This resistance is often mediated by membrane and enzymatic barriers.
- Alterations in outer membrane porins (OmpC-OmpF orthologues) are frequently observed in resistant strains.
Purpose of the Study:
- To investigate the role of outer membrane porin alterations in bacterial resistance to beta-lactam antibiotics.
- To understand the functional impact of mutations in OmpC on antibiotic uptake.
- To highlight the importance of porin function in antibiotic impermeability resistance.
Main Methods:
- Analysis of gene expression and mutations in OmpC-OmpF orthologues from resistant Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates.
- Functional characterization of porin mutations, focusing on changes in the constriction region.
- Assessment of the impact of porin alterations on solute and antibiotic diffusion.
Main Results:
- Mutations in the OmpC gene were found to significantly alter porin function.
- Alterations in the constriction region of OmpC led to reduced lumen diameter and/or modified electrostatic fields.
- These porin modifications restrict the influx of beta-lactam antibiotics while allowing essential solute entry.
Conclusions:
- Outer membrane porin OmpC plays a critical role in the impermeability-resistance mechanisms of Enterobacteriaceae against beta-lactam antibiotics.
- Understanding porin function and developing methods to measure intracellular antibiotic concentrations are crucial for overcoming resistance.
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