Biofilm formation in pathogenic bacteria defends them from antibiotics and the host's immune system. In the course of our search for new inhibitors of biofilm formation in Mycobacterium species, we isolated the sesterterpenes ophiobolin K (1), 6-epi-ophiobolin K (2), and 6-epi-ophiobolin G (3) from a culture of marine-derived fungus of Emericella variecolor. Ophiobolins 1-3 inhibited biofilm formation of Mycobacterium smegmatis with MICs of 4.1-65 μM, whereas these compounds did not show antimicrobial activity at the concentrations that showed anti-biofilm formation activity. Ophiobolin K (1) was also effective against the biofilm formation of M. bovis BCG and was able to restore the antimicrobial activity of isoniazid against M. smegmatis by inhibiting biofilm formation.
Biofilm is an assemblage of microorganisms enclosed in a matrix of extracellular materials such as polysaccharide, 1) and relates to bacterial virulence, pathogenesis, and environmental survival. Indeed, microorganisms existing in biofilm have remarkably high resistance to antibiotics and the immune system of a host's life. [2][3][4][5] Therefore, investigation of the molecular mechanisms of biofilm formation and search for new substances counteracting such formation are becoming an attractive research area.Tuberculosis is one of the most common causes of morbidity and mortality in human immunodeficiency virus (HIV)-positive adults living in poverty.6) Although the role of biofilm formation in the pathogenesis of Mycobacterium (M.) tuberculosis remains unclear, many species of Mycobacterium including M. tuberculosis are known to form biofilm. Several studies suggested that biofilm formation may play an important role in the pathogenesis of M. ulcerans as a causative agent of chronic skin ulcers and the virulence of M. avium subspecies paratuberculosis as a potent risk factor for Crohn's disease. 7,8) In addition, it is speculated that novel molecular events and regulatory circuitries of biofilm formation would still exist in Mycobacterium species. For instance, the cell wall biosynthesis, especially biosynthesis of mycolic acids, is involved in the process of biofilm formation in M. smegmatis and M. tuberculosis. 9-11)On the other hand, the marine environment provides rich chemical and biological diversity and has been a source of potent drug leads. Bioactive compounds from marine organisms are also considered to be useful tools for identification of novel drug targets and biological functions in the cells and microorganisms. Our previous work focused on the discovery of anti-dormant mycobacterial substances from marine organisms, and we discovered several active compounds such as halicyclamines 12,13) (marine spongean macrocyclic alkaloid) and trichoderins 14) (novel aminolipopeptides from a marine sponge-derived Trichoderma sp.).On the basis of this background, we established a screening system searching for inhibitors of biofilm formation against Mycobacterium species. We rediscovered desferrioxamine E, a cyclic trihydroxamate siderophore, 15) from the culture of the marine-derived Actinomycete MS67 as an inhibitor of biofilm formation against M. smegmatis. In this paper, the selective inhibitory activity of biofilm formation and the action-mechanism of desferrioxamine E against Mycobacterium species are presented. MATERIALS AND METHODS MaterialsMiddlebrook 7H9 broth, Middlebrook 7H10 agar, and Middlebrook OADC Enrichment were obtained from BD (Franklin Lakes, NJ, U.S.A.). Artificial sea water (MARINE ART BR) was purchased from Osakayakken Co., Ltd. (Osaka, Japan). Isoniazid, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and other chemicals were obtained from Sigma (St. Louis, MO, U.S.A.).Isolation of Desferrioxamine E The actinomycete MS67 was isolated from marine sediment collected fro...
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