How beta-lactam antibiotics enter bacteria: a dialogue with the porins.
BACKGROUND: Multi-drug resistant (MDR) infections have become a major concern in hospitals worldwide. This study investigates membrane translocation, which is the first step required for drug action on internal bacterial targets. beta-lactams, a major antibiotic class, use porins to pass through the...
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doaj-44211e5135e5432ebc8d3b661c71dfb22020-11-25T02:38:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0145e545310.1371/journal.pone.0005453How beta-lactam antibiotics enter bacteria: a dialogue with the porins.Chloë E JamesKozhinjampara R MahendranAlexander MolitorJean-Michel BollaAndrey N BessonovMathias WinterhalterJean-Marie PagèsBACKGROUND: Multi-drug resistant (MDR) infections have become a major concern in hospitals worldwide. This study investigates membrane translocation, which is the first step required for drug action on internal bacterial targets. beta-lactams, a major antibiotic class, use porins to pass through the outer membrane barrier of Gram-negative bacteria. Clinical reports have linked the MDR phenotype to altered membrane permeability including porin modification and efflux pump expression. METHODOLOGY/PRINCIPAL FINDINGS: Here influx of beta-lactams through the major Enterobacter aerogenes porin Omp36 is characterized. Conductance measurements through a single Omp36 trimer reconstituted into a planar lipid bilayer allowed us to count the passage of single beta-lactam molecules. Statistical analysis of each transport event yielded the kinetic parameters of antibiotic travel through Omp36 and distinguishable translocation properties of beta-lactams were quantified for ertapenem and cefepime. Expression of Omp36 in an otherwise porin-null bacterial strain is shown to confer increases in the killing rate of these antibiotics and in the corresponding bacterial susceptibility. CONCLUSIONS/SIGNIFICANCE: We propose the idea of a molecular "passport" that allows rapid transport of substrates through porins. Deciphering antibiotic translocation provides new insights for the design of novel drugs that may be highly effective at passing through the porin constriction zone. Such data may hold the key for the next generation of antibiotics capable of rapid intracellular accumulation to circumvent the further development MDR infections.http://europepmc.org/articles/PMC2677626?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chloë E James Kozhinjampara R Mahendran Alexander Molitor Jean-Michel Bolla Andrey N Bessonov Mathias Winterhalter Jean-Marie Pagès |
spellingShingle |
Chloë E James Kozhinjampara R Mahendran Alexander Molitor Jean-Michel Bolla Andrey N Bessonov Mathias Winterhalter Jean-Marie Pagès How beta-lactam antibiotics enter bacteria: a dialogue with the porins. PLoS ONE |
author_facet |
Chloë E James Kozhinjampara R Mahendran Alexander Molitor Jean-Michel Bolla Andrey N Bessonov Mathias Winterhalter Jean-Marie Pagès |
author_sort |
Chloë E James |
title |
How beta-lactam antibiotics enter bacteria: a dialogue with the porins. |
title_short |
How beta-lactam antibiotics enter bacteria: a dialogue with the porins. |
title_full |
How beta-lactam antibiotics enter bacteria: a dialogue with the porins. |
title_fullStr |
How beta-lactam antibiotics enter bacteria: a dialogue with the porins. |
title_full_unstemmed |
How beta-lactam antibiotics enter bacteria: a dialogue with the porins. |
title_sort |
how beta-lactam antibiotics enter bacteria: a dialogue with the porins. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2009-01-01 |
description |
BACKGROUND: Multi-drug resistant (MDR) infections have become a major concern in hospitals worldwide. This study investigates membrane translocation, which is the first step required for drug action on internal bacterial targets. beta-lactams, a major antibiotic class, use porins to pass through the outer membrane barrier of Gram-negative bacteria. Clinical reports have linked the MDR phenotype to altered membrane permeability including porin modification and efflux pump expression. METHODOLOGY/PRINCIPAL FINDINGS: Here influx of beta-lactams through the major Enterobacter aerogenes porin Omp36 is characterized. Conductance measurements through a single Omp36 trimer reconstituted into a planar lipid bilayer allowed us to count the passage of single beta-lactam molecules. Statistical analysis of each transport event yielded the kinetic parameters of antibiotic travel through Omp36 and distinguishable translocation properties of beta-lactams were quantified for ertapenem and cefepime. Expression of Omp36 in an otherwise porin-null bacterial strain is shown to confer increases in the killing rate of these antibiotics and in the corresponding bacterial susceptibility. CONCLUSIONS/SIGNIFICANCE: We propose the idea of a molecular "passport" that allows rapid transport of substrates through porins. Deciphering antibiotic translocation provides new insights for the design of novel drugs that may be highly effective at passing through the porin constriction zone. Such data may hold the key for the next generation of antibiotics capable of rapid intracellular accumulation to circumvent the further development MDR infections. |
url |
http://europepmc.org/articles/PMC2677626?pdf=render |
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