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Outer Membrane Profiles of Clonally Related Klebsiella pneumoniae
Abstract:
Antimicrobial treatment of Klebsiella pneumoniae infections can be complicated by the existence of multiply-antibiotic resistant (multiresistant) strains carrying plasmids coding for extended-spectrum β-lactamases (ESBLs), AmpC-type β-lactamases (ACTBLs), or aminoglycoside-modifying enzymes. This situation has become an increasingly serious problem worldwide with incidences ranging from 5% in the United States (1) to 16% in Europe (2), and higher incidences have been reported for particular hospitals or areas due to nosocomial outbreaks (3). Additionally, it should be noted that a large proportion of ESBL-producing strains are also resistant to fluoroquinolones, probably because of mutations in the genes coding for the A subunits of topoisomerases II (DNA-gyrase) and IV. When ESBLs or ACTBLs expression is accompanied by a decreased permeability of the bacterial outer membrane (OM), a major increase in the MICs of β-lactams (including carbapenems in strains expressing ACTBLs) has been observed (4, 5). Similarly, a reduction in permeability also causes moderate increases in the MICs of fluoroquinolones (3, 5, 6). This decreased permeability is caused by the loss or reduced expression of porins, the nonspecific pore outer membrane proteins (OMPs), with the subsequent reductions of antibiotic influx and of access to the antibiotic target. Reduction of porin expression during antimicrobial treatment are caused by different mutations in the porin genes, including point mutations, small and large deletions, and interruption of porin genes by insertion sequences (7).
Insights
Multidrug-resistant Klebsiella pneumoniae poses a global threat. Reduced outer membrane permeability, often due to porin loss, significantly increases resistance to antibiotics like beta-lactams and fluoroquinolones.
Area of Science:
- Microbiology
- Infectious Diseases
- Antimicrobial Resistance
Background:
- Multiply-antibiotic resistant (multiresistant) Klebsiella pneumoniae strains, often carrying plasmids for extended-spectrum β-lactamases (ESBLs) or AmpC-type β-lactamases (ACTBLs), complicate treatment.
- Global incidences of these resistant strains are increasing, with significant prevalence in the US and Europe, and higher rates in nosocomial outbreaks.
- Resistance to fluoroquinolones is common in ESBL-producing strains, likely due to mutations affecting topoisomerase genes.
Purpose of the Study:
- To investigate the mechanisms contributing to increased antibiotic resistance in Klebsiella pneumoniae.
- To understand the role of outer membrane permeability and porin expression in antimicrobial resistance.
- To identify genetic factors leading to reduced porin expression.
Main Methods:
- Analysis of antibiotic resistance mechanisms in Klebsiella pneumoniae.
- Examination of the correlation between ESBL/ACTBL production and reduced outer membrane permeability.
- Investigation of mutations in porin genes leading to decreased porin expression.
Main Results:
- Decreased outer membrane permeability, caused by loss or reduced expression of porins, significantly increases minimum inhibitory concentrations (MICs) for β-lactams and fluoroquinolones.
- Reduced porin expression leads to decreased antibiotic influx and reduced access to intracellular targets.
- Mutations in porin genes, including point mutations, deletions, and insertion sequences, are responsible for the reduction in porin expression.
Conclusions:
- Reduced outer membrane permeability is a critical factor in the high-level resistance observed in multiresistant Klebsiella pneumoniae.
- Targeting porin expression or function could be a strategy to overcome antibiotic resistance in these pathogens.
- Understanding the genetic basis of porin loss is essential for developing new therapeutic approaches against Klebsiella pneumoniae infections.
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