Bacterial Genetics and Differentiation


  HEADDr MAZODIER Philippe / mazodier@pasteur.fr
  MEMBERSDr BENAROUDJ Nadia / FALORD Mélanie / GUYET Aurélie


  Annual Report

Streptomyces spp. are gram-positive, filamentous, soil bacteria of the order Actinomycetales. Their morphological differentiation is remarkable. The spores germinate to give a substrate mycelium, which then differentiates into an aerial mycelium that undergoes septation and differentiates into spores. Their metabolic differentiation is also amazing, with the synthesis of large numbers of diverse secondary metabolites. Streptomyces and closely related genera produce more than half of the 200 commercially available antibiotics.

One of the surprises brought by the genome sequencing of Streptomyces was that the best-studied species contain a number of cryptic genes clusters involved in secondary metabolism. If unknown genes are present at such extend, this should urge us to reassess the Streptomyces collections made during these last 50 years. They should contain an important unexplored reservoir of metabolic diversity that it would be very valuable to express.

Presently our main topic is ATP dependent proteolysis, in particular analysis of the Clp system. We have shown previously that ClpP proteolysis is involved in the global regulatory networks controlling secondary metabolism and morphological differentiation. The Clp system involves the protease ClpP, which by itself has only peptidase activity and ATPases chaperones ClpC, ClpX that have the capacity to recognize target proteins specifically and to unfold them in order to insert them in the ClpP proteolytic chamber, thus allowing a targeted protease activity.

The system is especially complex in Streptomyces with five-clpP, one clpX and two-clpC genes and there are evidences that some ClpP activity is indispensable for their survival.

Regulations at the transcription and post-translation levels. We have shown that clpP3clpP4 operon is under control of activator PopR, which is degraded by ClpP1P2 thus only expressed in a clpP1 mutant. clpP1clpP2 operon is under control of activator ClgR. Several other genes such as clpC1, lon, SCO5169 belong also to the ClgR regulon. We have shown degradation of ClpC1, Lon, ClgR or ArmX (a new transcription regulator) by ClpP1P2.

ADEP, a new antibiotic able to bind ClpP protein, and to induce proteolytic activity in absence of cohort ATPase ClpC was recently described at Bayer Inc. (Brötz-Oesterheltl et al Nature-Medicine 2005). As protein anarchistic degradation leads to the death of treated cell, ADEP is an antibiotic. ADEP is produced by Streptomyces hawaiiensis, due to our interest for the Streptomyces and Clp proteolysis that doubly challenges us.

We have evidences that ClpP3ClpP4 are not sensitive to ADEP. That could ensure a potent mechanism of resistance by substitution. Indeed, as described above the mere inhibition of clpP1P2 expression allows the strain to display ClpP3ClpP4.

mazodier.jpg

Broken lines indicate proteolytic degradation



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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