Inhibitory effect of isoniazid and orlistat combination on mycobacterial ES-31 serine protease in vitro and on the growth of M.tb bacilli in axenic culture.
BACKGROUND
Isoniazid and orlistat were reported to have inhibitory effect on mycobacterial ES-31 serine protease in vitro and bacterial cell growth in axenic culture.


OBJECTIVE
To study the cumulative effect and understand drug - drug interaction, if any, when isoniazid and orlistat used in combination.


METHODS
Inhibition of mycobacterial ES-31 serine protease by different combinations of orlistat and isoniazid together and individually were studied using azocasein assay. Inhibition of secretion of excretory secretory ES-31 antigen in Sautan culture medium was studied under axenic condition and growth of M. tuberculosis H37Ra bacilli by CFU count on LJ-medium.


RESULTS
Orlistat and isoniazid both showed inhibitory activity of ES-31 serine protease in in vitro as well as in vivo. Individually, isoniazid showed 90% inhibition at 200 ng/ml while orlistat at 250 ng/ml showed 65% inhibition of mycobacterial ES-31 serine protease in vitro. A combination of orlistat (250 ng/ml) and isoniazid (200 ng/ml) showed 86% inhibition in vitro while 73% inhibition was observed by orlistat (25 ng/ml) and isoniazid (200 ng/ml) on bacterial growth in axenic culture.


CONCLUSIONS
Significant inhibition by orlistat suggests that it could be tried in patients with intolerance to isoniazid or in those already developed isoniazid resistance. It may also be explored in the suspected TB patients as initial medication in place of antibiotics for clinical relief.
JB Tropical Disease Research Centre, Mahatma Gandhi Institute of Medical Sciences, Sevagram - 442 102, District - Wardha, Maharashtra.
Gauri
G
Wankhade
Vinita
V
Hutke
Pranita J
PJ
Waghmare
Arup Kr
AK
Misra
Sushil Kumar
SK
Varma
B C
BC
Harinath
D000995:Antitubercular Agents / Q000494:pharmacology; D061245:Axenic Culture / Q000379:methods*; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D007783:Lactones / Q000493:pharmacokinetics*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D000077403:Orlistat; D057057:Serine Proteases / Q000187:drug effects* / Q000378:metabolism
D000995:Antitubercular Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007783:Lactones; D000077403:Orlistat; D057057:Serine Proteases; D007538:Isoniazid