Industrial and Pharmaceutical Microbiology

Biography

Biography: Georgios Daletos

Abstract

Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB), is one of the leading causes of mortality and morbidity caused by pathogenic microorganisms. Treatment of TB is currently facing serious problems due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains. The latter is practically untreatable with the currently available anti-TB drugs on the market and thus that there is an urgent need for novel antibiotics against TB. During our ongoing search for new potential anti-TB drug leads, we investigated the endophytic fungus Mucor irregularis, which was isolated from the Cameroonian medicinal plant Moringa stenopetala. The ethyl acetate extract of M. irregularis yielded two flavonoid-type derivatives, chlorflavonin and dechlorflavonin, the latter only differing by the absence of a chlorine atom in the B ring. In contrast to dechlorflavonin, chlorflavonin exhibited strong growth inhibitory activity against M. tuberculosis, indicating that chlorination plays an important role for anti-TB activity. Importantly, chlorflavonin showed no cytotoxicity against the human fibroblast (MRC-5) and macrophage-like human acute monocytic leukemia (THP-1) cell lines up to concentrations of 100 μM. Mapping of resistance-mediating mutations revealed that chlorflavonin specifically inhibits the acetohydroxyacid synthase IIvB1, which mediates the first step in branched chain amino acids and pantothenic acid biosynthesis. Chlorflavonin displayed synergistic effects in combination with the first-line antibiotic isoniazid leading to a complete sterilization and no resistance in liquid culture during combination treatment. Moreover, chlorflavonin exhibited potent activity against XDR M. tuberculosis strains, which highlights the potential of this compound as a promising anti-TB agent.