HspX knock-out in Mycobacterium tuberculosis leads to shorter antibiotic treatment and lower relapse rate in a mouse model – A potential novel therapeutic target

Hu, Y., Liu, A., Menendez, M. C., Garcia, M. J., Oravcova, K. , Gillespie, S. H., Davies, G. R., Mitchison, D. A. and Coates, A. R.M. (2015) HspX knock-out in Mycobacterium tuberculosis leads to shorter antibiotic treatment and lower relapse rate in a mouse model – A potential novel therapeutic target. Tuberculosis, 95(1), pp. 31-36. (doi: 10.1016/j.tube.2014.11.002) (PMID:25481272)

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Abstract

Effective global tuberculosis control is hindered by the need for prolonged chemotherapy which leads to poor patient compliance. Therefore novel drug targets that shorten the duration of chemotherapy and reduce disease relapse rates are highly desirable. We have previously shown that HspX, an alpha-crystallin-like protein, is associated with growth suppression of Mycobacterium tuberculosis in mouse models. We determined to evaluate hspX as a novel target for controlling M. tuberculosis growth in combination with traditional antibiotic therapy in the Cornell mouse model. The hspX deletion mutant (ΔhspX) was used as a model of potential hspX inhibition. Normal BALB/c mice were infected with ΔhspX or the wild type (WT) strain. Three weeks after infection, the mice were treated with rifampicin, isoniazid and pyrazinamide for 14 weeks followed by 8 weeks of hydrocortisone. The effect of chemotherapy was measured by organ bacterial counts and the relapse rate. Antibiotic treatment of mice infected with ΔhspX resulted in faster visceral clearance; organs were disease free 8 weeks post-treatment for ΔhspX infection compared to 14 weeks for the WT strain. Disease relapse rate was significantly lower in ΔhspX infection (60.7%) compared to WT infection (92.6%). HspX may be a promising therapeutic target in combination with traditional antibiotic therapy to shorten the length of treatment and reduce disease relapse.

Item Type:Articles
Additional Information:This work was supported by the European Commission's Sev-enth Framework Programme (grant number 200999) and theInnovative Medicines Initiative Joint Undertaking resources ofwhich are composed offinancial contribution from the EuropeanUnion's Seventh Framework Programme (FP7/2007e2013) andEFPIA companies' in kind contribution (grant number 115337).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Oravcova, Dr Katarina
Authors: Hu, Y., Liu, A., Menendez, M. C., Garcia, M. J., Oravcova, K., Gillespie, S. H., Davies, G. R., Mitchison, D. A., and Coates, A. R.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Tuberculosis
Publisher:Elsevier
ISSN:1472-9792
ISSN (Online):1873-281X
Published Online:20 November 2014

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