[ODP19] 4. Genetics / Genomics / Biotechnology -d. Genetic manipulation and analysis, biotechnology and synthetic biology

[ODP-093] Mycobacterial protease clp is a promising anti-TB drug target

Takehiro Yamaguchi^1,2, Noriaki Samukawa¹, Yuriko Ozeki³, Sohkichi Matsumoto³, Shuhei Tomita¹ (¹Dept. Pharmacol., Grad. Sch. Med., Osaka City Univ., ²Dept. Bacteriol. I, Natl. Inst. Infect. Dis., ³Dept. Bacteriol., Grad. Sch. Med., Niigata Univ.)

Background: Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), is the world’s leading infections disease. Because of increasing emergence of drug-resistant Mtb, development of a novel anti-TB drug is required. Bacterial proteases are maintaining proteostasis and essential for bacterial survival. Here, we investigated whether bacterial proteases are feasible for targets of anti-TB drugs.
Methods and Results: Inducible knockdown strains of proteases (clp, ftsH or htrA) in Mycobacterium smegmatis mc2-155 were created by using clustered regularly interspaced short palindromic repeats interference (CRISPRi). Although gene knockdown of the proteases did not suppress bacterial growth, knockdown of htrA conferred resistance to isoniazid and knockdown of clp increased the susceptibility against isoniazid and rifampicin, traditional anti-TB drugs. Furthermore, checkerboard assay revealed the synergistic effect between cyclomarin A, a novel clp inhibitor, and anti-TB drugs.
Conclusions: Clp is a promising drug target for development of a novel anti-TB drug.