A breakthrough in the fight against multiresistance to antibiotics

Multiresistance to antibiotics is a major public health problem. In hospitals, multiresistant pathogens are the main obstacle hindering the control of nosocomial infections. One of the main ways of spreading such resistance is the transfer between bacteria of a class of particularly mobile elements, called integrons, which are carriers of these resistance factors. In a study published today ? in Nature, researchers at the Pasteur Institute and the CNRS have been able to identify the complex mechanisms which explain how these integrons are very efficiently transmitted from one bacterial population to another. This work offers a new approach to research into treatments intended to block the transmission of resistance from one type of bacteria to another.

 

 

Press release
Paris, may 23, 2006

 

 

Integrons are large mobile elements which can carry many of the genes involved in the adaptation of bacteria to their environment. Some of them are able to combine up to 8 different traits and transport them from one type of pathogenic bacteria to another. They also play a role in spreading antibiotic resistance. In order to block this dispersion capability, it is essential to obtain a detailed understanding of the mechanisms that govern this transfer process.

The teams at the Pasteur Institute and the CNRS, led by Deshmukh Gopaul and Didier Mazel, have used crystallographic methods to confirm the suitability of a model which had been proposed in a study carried out using genetic analyses in vivo (1). They saw that certain sequences of integrons could adopt a particular three-dimensional structure, a condition necessary for recognition by recombination enzymes (integrases) as well as for the exchange of genetic material. This same mechanism has also been proposed for the propagation of a bacteriophage carrier of a toxin in Vibrio cholerae (2).

This unique structure adopted by the DNA of the integrons as well as the interface that they form with the integrase become a potential target for drugs aimed at blocking the integron transfer. This observation opens the door to research into treatments intended to combat the alarming spread of antibiotic multiresistance.

«The unique feature about this new mechanism, Didier Mazel and Deshmukh Gopaul explain, is that recognition of the DNAs to integrate uses a code which until now we knew completely nothing about. Also, the extraordinary ability shown by the recombination enzymes to recognize these structures explains the outstanding success of these elements in the development of multiple forms of resistance to antibiotics. »

Sources

« Structural basis for broad DNA specificity in integron recombination» Nature 27 Avril 2006.
Douglas MacDonald (1), Gaëlle Demarre (2), Marie Bouvier (2), Didier Mazel (2) et Deshmukh Gopaul (1)

1. Laboratoire de Biochimie et Biophysique des Macromolécules, Institut Pasteur
2. Unité Plasticité du Génome Bactérien, Institut Pasteur-CNRS

(1) « Integron cassette insertion: a recombination process involving a folded single strand substrate », Embo Journal Décembre 2005
Marie Bouvier, Gaëlle Demarre et Didier Mazel
Unité Plasticité du Génome Bactérien, Institut Pasteur-CNRS

(2) « The single-stranded genome of phage CTX is the form used for integration into the genome of Vibrio cholerae » , Molecular Cell, Août 2005,
Marie-Eve Val (1,2), Marie Bouvier (3), Javier Campos (4), David Sherratt (5), François Cornet (2), Didier Mazel (3), François-Xavier Barre (1,2)
1. Centre de Génétique Moléculaire, CNRS Gif sur Yvette Cedex, France
2. Laboratoire de Microbiologie et de Génétique Moléculaires, CNRS Toulouse , France
3. Unité Postulante Plasticité du Génome Bactérien, CNRS-Institut Pasteur, France
4. Departamento de Genetica, Centro Nacional de Investigaciones Cientificas, Havana, Cuba
5. Division of Molecular Genetics, University of Oxford, United Kingdom

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