Background Due to the rising incidence of tuberculosis (TB) worldwide and the emergence of multidrug resistant (MDR) strains, the development of new antituberculous drugs to reduce the duration of the treatment and fight MDR-TB is urgently needed. The aim of this study is to assess the antimycobacterial activity of natural products recently isolated from lichens, based on the scaffold of usnic acid, which is reported to have antimycobacterial properties in vitro on susceptible and resistant strains, but because of its rapid metabolism and toxicity prevents further exploitation. Methods 31 lichen compounds were screened for antimycobacterial activity. Stock solutions were prepared in dimethil sulfoxide and the final testing concentrations ranged from 64 to 0,25 µg/ml. Minimal inhibitory concentrations (MICs) were evaluated by the microplate Alamar blue assay (MABA) on M. tuberculosis H37Rv, isoniazid resistant (IHN-R) and susceptible (IHN-S) clinical isolates, all confirmed by genotypic and phenotypic tests. Isoniazid was used as a control and the experiments were performed in duplicate. Results The potential of new derivatives at the triketone moiety of usnic acid, the portion that causes toxicity, was evaluated. Out of the 31 compounds, 11 with a MIC ≤32 µg/ml were selected: usnic acid (MIC 32 µg/ml) and 10 of its derivatives. 3 derivatives showed MICs between 8 and 16 µg/ml, 2 of them with MIC 8 µg/ml stable in H37Rv, IHN-R and IHN-S clinical isolates. The most active compounds (PS14, PS18 and PS19) bear an heterocyclic portion, linked as enamine or hydrazone to the benzofurandione scaffold. Conclusion Two lichen compounds seem to be active against M. tuberculosis H37Rv, IHN-R and IHN-S isolates. These results show that usnic acid derivatives have an higher activity than usnic acid itself, which is an active compound, but toxic. Further studies must be done against rifampicin resistant strains to evaluate the real significance of such compounds for MDR-TB.
Antimycobacterial activity of new derivatives of the lichen metabolite, (+)-usnic acid / I. Festoso, E. Borroni, L. Verotta, M. Bruno, E. Tortoli, D.M. Cirillo. ((Intervento presentato al convegno Tbpannet Mid-term meeting tenutosi a Milano nel 2011.
Antimycobacterial activity of new derivatives of the lichen metabolite, (+)-usnic acid
L. Verotta;M. Bruno;
2011
Abstract
Background Due to the rising incidence of tuberculosis (TB) worldwide and the emergence of multidrug resistant (MDR) strains, the development of new antituberculous drugs to reduce the duration of the treatment and fight MDR-TB is urgently needed. The aim of this study is to assess the antimycobacterial activity of natural products recently isolated from lichens, based on the scaffold of usnic acid, which is reported to have antimycobacterial properties in vitro on susceptible and resistant strains, but because of its rapid metabolism and toxicity prevents further exploitation. Methods 31 lichen compounds were screened for antimycobacterial activity. Stock solutions were prepared in dimethil sulfoxide and the final testing concentrations ranged from 64 to 0,25 µg/ml. Minimal inhibitory concentrations (MICs) were evaluated by the microplate Alamar blue assay (MABA) on M. tuberculosis H37Rv, isoniazid resistant (IHN-R) and susceptible (IHN-S) clinical isolates, all confirmed by genotypic and phenotypic tests. Isoniazid was used as a control and the experiments were performed in duplicate. Results The potential of new derivatives at the triketone moiety of usnic acid, the portion that causes toxicity, was evaluated. Out of the 31 compounds, 11 with a MIC ≤32 µg/ml were selected: usnic acid (MIC 32 µg/ml) and 10 of its derivatives. 3 derivatives showed MICs between 8 and 16 µg/ml, 2 of them with MIC 8 µg/ml stable in H37Rv, IHN-R and IHN-S clinical isolates. The most active compounds (PS14, PS18 and PS19) bear an heterocyclic portion, linked as enamine or hydrazone to the benzofurandione scaffold. Conclusion Two lichen compounds seem to be active against M. tuberculosis H37Rv, IHN-R and IHN-S isolates. These results show that usnic acid derivatives have an higher activity than usnic acid itself, which is an active compound, but toxic. Further studies must be done against rifampicin resistant strains to evaluate the real significance of such compounds for MDR-TB.
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