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Title: Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis
Authors: Rao, S.P.S.
Lakshminarayana, S.B.
Kondreddi, R.R.
Herve, M.
Camacho, L.R.
Bifani, P.
Kalapala, S.K.
Jiricek, J.
Ma, N.L.
Tan, B.H.
Ng, S.H.
Nanjundappa, M.
Ravindran, S.
Seah, P.G.
Thayalan, P.
Lim, S.H.
Lee, B.H.
Goh, A.
Barnes, W.S.
Chen, Z.
Gagaring, K.
Chatterjee, A.K.
Pethe, K.
Kuhen, K.
Walker, J.
Feng, G.
Babu, S.
Zhang, L.
Blasco, F.
Beer, D.
Weaver, M.
Dartois, V.
Glynne, R.
Dick, T. 
Smith, P.W.
Diagana, T.T.
Manjunatha, U.H.
Issue Date: 4-Dec-2013
Citation: Rao, S.P.S., Lakshminarayana, S.B., Kondreddi, R.R., Herve, M., Camacho, L.R., Bifani, P., Kalapala, S.K., Jiricek, J., Ma, N.L., Tan, B.H., Ng, S.H., Nanjundappa, M., Ravindran, S., Seah, P.G., Thayalan, P., Lim, S.H., Lee, B.H., Goh, A., Barnes, W.S., Chen, Z., Gagaring, K., Chatterjee, A.K., Pethe, K., Kuhen, K., Walker, J., Feng, G., Babu, S., Zhang, L., Blasco, F., Beer, D., Weaver, M., Dartois, V., Glynne, R., Dick, T., Smith, P.W., Diagana, T.T., Manjunatha, U.H. (2013-12-04). Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Science Translational Medicine 5 (214) : -. ScholarBank@NUS Repository.
Abstract: New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drugsensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.
Source Title: Science Translational Medicine
ISSN: 19466234
DOI: 10.1126/scitranslmed.3007355
Appears in Collections:Staff Publications

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