Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model

• Published in: Journal of antimicrobial chemotherapy 2015-11, Vol.70 (11), p.3070-3073
• Main Authors: Knudson, Susan E, Awasthi, Divya, Kumar, Kunal, Carreau, Alexandra, Goullieux, Laurent, Lagrange, Sophie, Vermet, Hélène, Ojima, Iwao, Slayden, Richard A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antibiotics; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacology; Bacteria; Bacterial infections; Bacterial Proteins - antagonists & inhibitors; Benzimidazoles - administration & dosage; Benzimidazoles - pharmacology; Cell division; Cell Division - drug effects; Cell Survival - drug effects; Cercopithecus aethiops; Cytoskeletal Proteins - antagonists & inhibitors; Disease Models, Animal; Drug Stability; Inactivation, Metabolic; Inhibitor drugs; Injections, Intraperitoneal; Isoniazid - administration & dosage; Isoniazid - pharmacology; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Original Research; Treatment Outcome; Tuberculosis; Tuberculosis - drug therapy; Vero Cells
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkv226

The increasing number of clinical strains resistant to one or more of the front-line TB drugs complicates the management of this disease. To develop next-generation benzimidazole-based FtsZ inhibitors with improved efficacy, we employed iterative optimization strategies based on whole bacteria potency, bactericidal activity, plasma and metabolic stability and in vivo efficacy studies. Candidate benzimidazoles were evaluated for potency against Mycobacterium tuberculosis H37Rv and select clinical strains, toxicity against Vero cells and compound stability in plasma and liver microsomes. The efficacy of lead compounds was assessed in the acute murine M. tuberculosis infection model via intraperitoneal and oral routes. MICs of SB-P17G-A33, SB-P17G-A38 and SB-P17G-A42 for M. tuberculosis H37Rv and select clinical strains were 0.18-0.39 mg/L. SB-P17G-A38 and SB-P17G-A42 delivered at 50 mg/kg twice daily intraperitoneally or orally demonstrated efficacy in reducing the bacterial load by 5.7-6.3 log10 cfu in the lungs and 3.9-5.0 log10 cfu in the spleen. SB-P17G-A33 delivered at 50 mg/kg twice daily intraperitoneally or orally also reduced the bacterial load by 1.7-2.1 log10 cfu in the lungs and 2.5-3.4 log10 cfu in the spleen. Next-generation benzimidazoles with excellent potency and efficacy against M. tuberculosis have been developed. This is the first report on benzimidazole-based FtsZ inhibitors showing an equivalent level of efficacy to isoniazid in an acute murine M. tuberculosis infection model.