Novel inhibitors of M. tuberculosis from a library of known drugs
A medium-throughput assay was set-up to identify novel inhibitors of M. tuberculosis from a library of known drugs[1] with proven suitability and safety as human therapeutics. 1514 compounds screened, out of which 53 exhibited inhibitory properties against M. tuberculosis at a concentration < 5 μM. Among these, 17 were novel inhibitors while 36 were known tuberculosis drugs or had been previously described as possessing anti-tuberculosis activity. Five compounds were selected as those which represent the most promising starting points for new anti-tuberculosis agents. While other drugs among these were not capable of completely preventing growth of the bacteria, only thiostrepton appeared to have a bacteriocidal effect. Pyrvinium pamoate and pentamide did not result in complete inhibition of growth compared to the untreated control at concentrations up to 20 μM, although they inhibited growth of intracellular bacteria to some extent at concentrations above 2.5 μM. Nialamide inhibted growth of intracellular bacteria at 10 μM, while Primaquine and Thiostrepton were inhibitory at 5 μM. Thiostrepton also had some bactericidal activity at 10 μM, reducing the initial colony count by 4 fold.
Use of thiostrepton as an anti-mycobacterial agent has also been claimed in a patent application[2] filed by EISAI CO LTD [JP]. Thiostrepton is an inducer of tipA, a gene that controls the bacterial transcription regulators, TipAL and TipAS, members of the MerR proteins that are central regulators in multidrug resistance.[3]
Liye Pharmaceutical Co., Ltd., has claimed medicinal application of clofazimine for treating tuberculosis[4]. Clofazimine preparation can inhibit Mycobacterium tuberculosis, even multidrug resistant Mycobacterium tuberculosis with resistance to isoniazid and rifampicin, by disturbing nucleic acid metab. and energy metab. According to the inventors, clofazimine is unlikely to induce drug resistance in Mycobacterium tuberculosis.
7-(3-amino-4-oxime)-1-piperidyl-containing fluoroquinolone and composition containing the same has been claimed in a patent application[5] filed by Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Zhejiang Starry Pharmaceutical Co., Ltd. The composition may be useful for control of active tuberculosis, single-drug resistant tuberculosis and multiple-drug resistant tuberculosis, pulmonary tuberculosis, extra-pulmonary tuberculosis, and tuberculosis in skeleton, joint, lymph node and intestinal tract etc.
Key Words: multidrug resistant tuberculosis, extensively drug resistant tuberculosis, multidrug resistant TB, extensively drug resistant TB, MDR TB, XDR TB, mycobacterium tuberculosis, mycobacterial infection, literature, research, publications, patents.
Key Words: multidrug resistant tuberculosis, extensively drug resistant tuberculosis, multidrug resistant TB, extensively drug resistant TB, MDR TB, XDR TB, mycobacterium tuberculosis, mycobacterial infection, literature, research, publications, patents.
[1] New Anti-tuberculosis Agents Amongst Known Drugs. Kathryn E.A et al., Tuberculosis, Volume 89, Issue 5, (2009) Pages 364-370 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981832/
[2] WO0154693 (A1) ― 2001-08-02
[4] CN 101658523 A 3 Mar 2010, 8pp. (Chinese).
[5] CN 101863876 A 20 Oct 2010, 7pp. (Chinese)
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