Journal Article

How β-Lactam Antibiotics Enter Bacteria: A Dialogue with the Porins

Pagès, Jean-Marie, Winterhalter, Mathias, Mahendran, Kozhinjampara R., Molitor, Alexander, James, Chloë E., Bessonov, Andrey N., Bolla, Jean-Michel

2009

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aerogenes / Amides / Anti-Bacterial Agents - metabolism / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteria / Bacterial infections / beta-Lactams - metabolism / beta-Lactams - pharmacology / Biochemistry / Biochemistry/Membrane Proteins and Energy Transduction / Biological Transport - drug effects / Campylobacter jejuni / Cefepime / Conductance / Drug development / Drug resistance / Drugs / E coli / Efflux / Engineering schools / Enterobacter aerogenes / Ertapenem / Escherichia coli / Escherichia coli - drug effects / Escherichia coli - metabolism / Escherichia coli Proteins - metabolism / Gram-negative bacteria / Infections / Infectious diseases / Infectious Diseases/Antimicrobials and Drug Resistance / Killing / Kinetics / Klebsiella pneumoniae / Lipid Bilayers - metabolism / Lipids / Membrane permeability / Membranes / Microbiology/Microbial Physiology and Metabolism / Molecular biology / Multidrug resistance / Mutation / Nosocomial infections / Outer membrane proteins / Permeability / Pharmacology / Pharmacology/Drug Resistance / Polyamines / Porins / Porins - metabolism / Proteins / Resistance / Statistical analysis / Studies / Substrates / Translocation / Transport / β-Lactam antibiotics