Review – Lichen-Associated Bacteria as a Hot Spot of Chemodiversity: Focus on Uncialamycin, a Promising Compound for Future Medicinal Applications
Introduction ! Despite significant treatment advances, diseases such as cancer and microbial infections remain major public health issues due to the emergence of antibiotic resistance and the weak efficiency of current anticancer therapies. Therefore, biotechnological advances and the search of more specific and effective drugs are important challenges for pharmaceutical companies worldwide. The recent discovery of teixobactin from uncultivated soil bacteria highlights the unexplored microbial
... explored microbial sources as treasure chests for the access to new interesting bioactive drugs  . Among underexplored sources, lichens are unique and are classically described as a symbiotic association between a photobiont (green alga and/or cyanobacterium) and a mycobiont. Most lichens are outstanding in their capacities to produce specific secondary metabolites that present biological activities, e.g., antioxidant, cytotoxic, and antimicrobial activities    . These organisms were also known to represent habitats for diverse lichenicolous fungi, with a high biosynthetic potential [9, 10]. Recent molecular approaches have also demonstrated the high diversity of lichen-associated bacterial communities that comprise millions of bacterial cells per gram of lichen thallus            . These associated organisms form stable and specific communities and thus represent as a whole a third partner of the lichens symbiosis  . They particularly colonize hydrophilic surfaces of lichens and are also incorporated within the extracellular fungal matrix  . These bacteria could either live as biofilm-like structures or as individual colonies  . These communities were characterized by culture-independent methods (e.g., pyrosequencing and FISH/CLSM) [12-15, 17, 18, 20, 21, 24-26] and culture-dependent approaches [11, 13,           . While proteobacteria usually dominate the bacterial community, members of other groups are present as well, in particular Actinobacteria, Bacteroidetes, Acidobacteria. In a recent review, we focused on the diversity of these communities, particularly in the point of view of the presence of biotechnologically interesting bacteria  . These species-specific diversity patterns of bacteria associated with lichens are influenced by various parameters such as extrinsic factors (e.g., exposure, substrate type, and location) and intrinsic factors (e.g., lichen species, age and part of the lichen thallus, and chemical composition of the lichen) [16-18, 23, 26, 38-40] (l " Fig. 1 ). Indeed some studies highlighted the prevalence of Abstract ! This review presents the state of knowledge on the medicinal potential of bacteria associated with lichens. In fact, besides the classical symbiotic partners (photobiont and mycobiont) forming the lichen thallus, associated bacteria have been recently described as a third partner. Various studies demonstrated the diversity of these communities with a predominance of Alphaproteobacteria. Bacterial groups more relevant for sec-ondary metabolite synthesis have also been revealed. This article summarizes studies reporting the abilities of these communities to produce metabolites with relevant bioactivities. The biotechnological interest of these bacteria for drug discovery is highlighted regarding the production of compounds with therapeutic potential. Special focus is given to the synthesis of the most promising compound, uncialamycin, a potent enediyne isolated from a Streptomyces sp. associated with Cladonia uncialis.