Modulation of isoniazid susceptibility of mycobacterial strains by different flavonoids

The increasing emergence of multidrug-resistant (MDR) tuberculosis requests the development of new drugs to combat infections associated with mycobacteria. Poor patient compliance due to significant side effects of long TB therapies often lead to deadly MDR bacteria [1].

In the course of this project, several flavonoids without significant antimycobacterial activity at the tested concentrations were screened for their ability to decrease the minimum inhibitory concentrations (MICs) of the first-line anti-TB drug isoniazid (INH) against different mycobacterial strains. Flavonoids with different substitution patterns were tested to examine structure-activity-relationships (SARs) of these compounds. To find out more about the variations between different mycobacterial strains, we used Mycobacterium smegmatis (ATCC 14468), M. smegmatis mc²155 (ATCC 700084), M. smegmatis mc²2700 and M. fortuitum (ATCC 6841) for our assays. We could observe the most intense synergistic effects in M. smegmatis mc²155 whereas the tendency of INH-potentialization by certain flavonoids stayed the same with each strain. Myricetin turned out to be the most efficient intensifier of INH susceptibility in all tested strains, followed by quercetin. SARs of flavonoids as INH activity modulators indicate that they overlap with SARs for their antioxidant properties, however, the potentialization of INH cannot only be explained by antioxidative activity.

Acknowledgements: Funded by Doc-Fforte 22076 (Austrian Academy of Sciences), Dr. Jose A. Ainsa (Universidad de Zaragoza) for scientific advice.

References: [1] Zhang, Y. et al. (2006) Drug Discov Today 11: 21–27.