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Infection and Immunity, October 2009, p. 4275-4283, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00609-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Burkholderia pseudomallei Isocitrate Lyase Is a Persistence Factor in Pulmonary Melioidosis: Implications for the Development of Isocitrate Lyase Inhibitors as Novel Antimicrobials {triangledown} ,{dagger}

Erin J. van Schaik, Marina Tom, and Donald E. Woods*

Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary Health Science Centre, 3330 Hospital Drive NW, Calgary, Alberta T2T 4N1, Canada

Received 29 May 2009/ Accepted 10 July 2009

Burkholderia pseudomallei, the causative agent of melioidosis, has often been called the great "mimicker," and clinical disease due to this organism may include acute, chronic, and latent pulmonary infections. Interestingly, chronic pulmonary melioidosis is often mistaken for tuberculosis, and this can have significant consequences, as the treatments for these two infections are radically different. The recurrent misdiagnosis of melioidosis for tuberculosis has caused many to speculate that these two bacterial pathogens use similar pathways to produce latent infections. Here we show that isocitrate lyase is a persistence factor for B. pseudomallei, and inhibiting the activity of this enzyme during experimental chronic B. pseudomallei lung infection forces the infection into an acute state, which can then be treated with antibiotics. We found that if antibiotics are not provided in combination with isocitrate lyase inhibitors, the resulting B. pseudomallei infection overwhelms the host, resulting in death. These results suggest that the inhibition of isocitrate lyase activity does not necessarily attenuate virulence as previously observed for Mycobacterium tuberculosis infections but does force the bacteria into a replicating state where antibiotics are effective. Therefore, isocitrate lyase inhibitors could be developed for chronic B. pseudomallei infections but only for use in combination with effective antibiotics.

* Corresponding author. Mailing address: Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. Phone: (403) 220-2564. Fax: (403) 210-8504. E-mail: woods{at}ucalgary.ca

{triangledown} Published ahead of print on 20 July 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: S. R. Blanke

Infection and Immunity, October 2009, p. 4275-4283, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00609-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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