title: Burkholderia pseudomallei isocitrate lyase is a persistence factor in pulmonary melioidosis: implications for the development of isocitrate lyase inhibitors as novel antimicrobials.
abstract: 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.
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: van Schaik
authors.forename: Marina
authors.initials: M
authors.lastname: Tom
authors.forename: Donald E
authors.initials: DE
authors.lastname: Woods
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016957:Burkholderia pseudomallei / Q000201:enzymology* / Q000472:pathogenicity; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007522:Isocitrate Lyase / Q000037:antagonists & inhibitors* / Q000502:physiology; D007928:Lethal Dose 50; D008168:Lung / Q000382:microbiology; D008554:Melioidosis / Q000188:drug therapy* / Q000382:microbiology*; D051381:Rats; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007522:Isocitrate Lyase