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

作者：Hu Yanmin^*; Liu Alexander; Menendez Maria C; Garcia Maria J; Oravcova Katarina; Gillespie Stephen H; Davies Gerry R; Mitchison Denis A; Coates Anthony R M

来源：Tuberculosis, 2015, 95(1): 31-36.

DOI：10.1016/j.tube.2014.11.002

• Mycobacterium tuberculosis
• hspX knock-out mutant
• Treatment
• Mouse model

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 (Delta hspX) was used as a model of potential hspX inhibition. Normal BALB/c mice were infected with DhspX 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 Delta hspX resulted in faster visceral clearance; organs were disease free 8 weeks posttreatment for Delta hspX infection compared to 14 weeks for the WT strain. Disease relapse rate was significantly lower in Delta hspX 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.

• 出版日期2015-1