Bis-biguanide dihydrochloride inhibits intracellular replication of M. tuberculosis and controls infection in mice.
While there is an urgent need to develop new and effective drugs for treatment of tuberculosis (TB) and multi-drug resistant TB (MDR-TB), repurposing FDA (U.S. Food and Drug Administration) -approved drugs for development of anti-TB agents may decrease time and effort from bench to bedside. Here, we employed host cell-based high throughput screening (HTS) assay to screen and characterize FDA-approved, off-patent library drugs for anti-Mycobacterium tuberculosis (MTB) activities. The cell-based HTS allowed us to identify an anti-cancer drug of bis-biguanide dihydrochloride (BBD) as potent anti-mycobacteria agent. Further characterization showed that BBD could inhibit intracellular and extracellular growth of M. smegmatis and slow-growing M. bovis BCG. BBD also potently inhibited replication of clinically-isolated MTB and MDR-TB strains. The proof-of-concept study showed that BBD treatment of MTB-infected mice could significantly decrease CFU counts in the lung and spleen. Notably, comparative evaluation showed that MTB CFU counts in BBD-treated mice were lower than those in rifampicin-treated mice. No apparent BBD side effects were found in BBD-treated mice. Thus, our findings support further studies to develop BBD as a new and effective drug against TB and MDR-TB.
Unit of anti-tuberculosis immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
Hongbo
H
Shen
Department of Medical Microbiology and Parasitology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Feifei
F
Wang
Department of Microbiology, Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China.
Gucheng
G
Zeng
Department of Microbiology/Immunology, and Center for Primate Biomedical Research, University of Illinois College of Medicine, 835 S. Wolcott Avenue, MC790 Chicago, IL 60612, United States.
Ling
L
Shen
Department of Microbiology and Immunology, University of Illinois College of Medicine, 835 S. Wolcott Avenue, MC790 Chicago, IL 60612, United States.
Han
H
Cheng
Department of Microbiology/Immunology, and Center for Primate Biomedical Research, University of Illinois College of Medicine, 835 S. Wolcott Avenue, MC790 Chicago, IL 60612, United States.
Dan
D
Huang
Department of Microbiology/Immunology, and Center for Primate Biomedical Research, University of Illinois College of Medicine, 835 S. Wolcott Avenue, MC790 Chicago, IL 60612, United States.
Richard
R
Wang
Department of Microbiology and Immunology, University of Illinois College of Medicine, 835 S. Wolcott Avenue, MC790 Chicago, IL 60612, United States.
Lijun
L
Rong
Department of Microbiology/Immunology, and Center for Primate Biomedical Research, University of Illinois College of Medicine, 835 S. Wolcott Avenue, MC790 Chicago, IL 60612, United States.|CAS Institut Pasteur of Shanghai, Shanghai 200031, China.
Zheng W
ZW
Chen
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001645:Biguanides / Q000008:administration & dosage* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D009163:Mycobacterium bovis / Q000187:drug effects; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D001645:Biguanides