Antibacterial Agents

Head of Unit: Marc Galimand



The Antibacterial Agents Unit studies the genetic support, biochemical mechanisms, heterospecific expression, evolution and dissemination of antibiotic resistance in bacterial pathogens for humans ; in particular : enterococci and glycopeptides, and resistance to ß-lactams and aminoglycosides in Gram negative bacilli. It has also developed trans-kingdom gene transfer from bacteria to mammalian cells.






Glycopeptide resistance in Enterococcus and Staphylococcus

We have previously shown that glycopeptide resistance in enterococci results from the production of modified peptidoglycan precursors ending in D-alanyl-D-lactate or D-Ala-D-serine to which glycopeptides exhibit low binding affinities. We are currently studying the inducible expression of resistance due to the presence of a two-component regulatory system.


Resistance to aminoglycosides in Gram negative bacilli

There are three known mechanisms of resistance to aminoglycosides in human pathogens: (i) decreased intracellular accumulation of the antibiotic, (ii) modification of the ribosomal target, and (iii) enzymatic modification of the drug. We have detected an additional mechanism which involves post-transcriptional methylation of ribosomal RNA. This mechanism confers high level resistance to nearly all aminoglycosides in Gram negative bacteria. The corresponding gene is part of a transposon borne by a self-transferable plasmid which accounts for its global dissemination in various species of enterobacteria. The methylase has been purified and crystallised. Resistance by efflux in Acinetobacter is also being studied.


Intracellular bacteria deliver DNA into mammalian cells


We have obtained gene transfer in vitro from intracellular bacteria to mammalian non phagocytic cells. The Escherichia coli used to deliver DNA were made invasive and engineered to lyse upon entry in the cell. We have reported that wild intracellular human pathogens, such as Listeria monocytogenes and Shigella flexneri, mediate efficient transfer of functional genes into epithelial and macrophage cell lines. We are currently using the bacterial vectors for gene therapy and stimulation of mucosal immunity.