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PEDS Advance Access published online on March 24, 2005
Protein Engineering Design and Selection, doi:10.1093/protein/gzi008
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received November 24, 2004
Revised February 4, 2005
Accepted February 8, 2005

Article

Peptide inhibitors of the essential cell division protein FtsA

Catherine Paradis-Bleau 1, François Sanschagrin 1, and Roger C. Levesque 1*

1 Département de Biologie Médicale, Université Laval, Sainte-Foy, Québec, G1K 7P4, Canada

* To whom correspondence should be addressed.
Roger C. Levesque, E-mail: rclevesq{at}rsvs.ulaval.ca


  Abstract

The revolutionary era of antibiotics has been overwhelmed by the evolutionary capacity of microorganisms such as Pseudomonas aeruginosa to develop resistance to all classes of antibiotics. In the perspective of identifying new antimicrobials using novel strategies, we targeted the essential and highly conserved FtsA protein from the bacterial cell division machinery of P.aeruginosa. In a series of experiments we cloned, overproduced and purified the FtsA and FtsZ proteins. Expression of FtsA into Escherichia coli cells led to its accumulation in inclusion bodies. We developed a protocol permitting the purification and refolding of enzymatically active FtsA hydrolysing ATP. The purified enzyme was used to screen for peptide inhibitors of ATPase activity using phage display. Selective biopanning assays were done and phages were eluted using ATP, a non-hydrolysable ATP analogue and the protein FtsZ known to interact with FtsA in the divisome during the process of bacterial cell division. We identified two consensus peptide sequences interacting with FtsA and a competitive ELISA was used to identify peptides having high affinity for the target protein. Five of the six peptides synthesized showed specific inhibition of ATPase activity of FtsA with IC50 values between 0.7 and 35 mM. Discovery of peptides inhibiting the essential cell division machinery in bacteria is the first step for the future development of antimicrobial agents via peptidomimetism.

Keywords: FtsA; FtsZ; inhibitory peptides; phage display; Pseudomonas aeruginosa.
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