Elucidation of the mode of action of a furanone based antituberculosis compound

[摘要] ENGLISH ABSTRACT: The prevalence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) Mycobacteriumtuberculosis has been increasing to alarming levels globally. This has been exacerbated bytuberculosis (TB) co-infection with HIV where the epidemic is endemic. South Africa as a developingcountry is hit hard by TB and efforts to develop TB drugs that are compatible with anti-retroviralmedication and also effective against MDR/XDR, could help shorten the treatment duration of thecurrent TB treatment regimens. This thesis presents the identification and characterisation of a novelfuranone based compound (F1082) and its derivatives as leads for anti-TB drug development.Furanones are generally known for an array of biological activities ranging from antibacterial,antifungal and antitumor.F1082 has an aromatic benzene structure and was identified from screening synthetic compoundsagainst M. tuberculosis. It is potent against M. tuberculosis at minimum inhibitory concentration(MIC) of 8 μg/ml. It is selective for mycobacteria since it did not inhibit the growth of Gram-positiveand Gram-negative bacteria at concentrations five times the MIC for M. tuberculosis. F1082 isgenerally bacteriostatic around MIC concentrations in its effects against M. tuberculosis however; itmay be bactericidal at higher concentrations. It is as effective against MDR, XDR and clinical isolatesof M. tuberculosis at the same concentration as the M. tuberculosis H37Rv reference strain. Thissuggests that F1082 may have a different mechanism of action compared to current TB drugs. It hasbeen shown to have no antagonistic effect with the first-line anti-TB drugs and it has been shown tosynergize with rifampicin by reducing the MIC of rifampicin. A drawback of F1082 is that it iscytotoxic to human cell lines, but this is presently being addressed through the synthesis of analoguesthat have shown improved activity and less cytotoxicity. The synthesis of more than 40 analogues hasled to identification of 4 compounds that have more than five times higher activity and more than 100times less cytotoxicity against human cell-lines.Microarray analyses have identified possible metabolic pathway/s in M. tuberculosis that is/areaffected by F1082. One subset of genes which showed the most prominent alteration encodes thesiderophores, which are involved with iron homeostasis in the M. tuberculosis bacillus. Of thesegenes, 7 were of interest (mbtB, mbtC, mbtD, mbtE, mbtF, mbtH and bfrB) as they all fall in the samecluster and are involved in iron acquisition. Due to the involvement of iron we also show that F1082generates oxidative stress that is metal (iron) dependent. From the results we conclude that F1082 is apromising antituberculosis lead compound with unique target properties and also specificity againstmycobacteria.

[发布机构] Stellenbosch University