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JAC Advance Access originally published online on December 24, 2008
Journal of Antimicrobial Chemotherapy 2009 63(3):451-457; doi:10.1093/jac/dkn507
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Morphological features and signature gene response elicited by inactivation of FtsI in Mycobacterium tuberculosis

Richard A. Slayden* and John T. Belisle

Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA

Received 25 August 2008; returned 21 October 2008; revised 5 November 2008; accepted 18 November 2008

* Corresponding author. Tel: +1-970-491-2902; Fax: +1-970-491-1815; E-mail: richard.slayden{at}colostate.edu

Objectives: Universally conserved events in cell division provide the opportunity for the development of novel chemotherapeutics against Mycobacterium tuberculosis. The aim of this study was to use the β-lactam antimicrobials cefalexin and piperacillin to inhibit FtsI and characterize the morphological changes and global transcriptional activities of genes to identify a signature response to FtsI inactivation.

Methods: Cefalexin and piperacillin were used to block cell division, and microscopy was used to evaluate the effects on bacterial morphology and ultrastructure. Global transcriptional analysis was performed to determine the impact of FtsI inhibition on cell cycle processes and to identify molecular markers.

Results: Inhibition of FtsI with cefalexin and piperacillin resulted in filamentous cells with multiple concentric rings and occasional branching as visualized by light and electron microscopy. Whole genome microarray-based transcriptional profiling and transcriptional mapping allowed the evaluation of cell cycle processes in response to inhibition of FtsI and characterization of transcriptional response and cell cycle processes.

Conclusions: This study substantiated that FtsZ-ring constriction and septal resolution require the transpeptidase activity of FtsI, making FtsI essential for cell division in M. tuberculosis. Therefore, FtsI is a target for drug discovery, and these studies provided a molecular signature of FtsI inactivation that can be applied to screening strategies for novel FtsI inhibitors.

Keywords: M. tuberculosis , cell division , microarray , cefalexin , piperacillin


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