## 2 Environmental Cues and Co-Cultivation
### Synergistic Interplay among Microorganisms  
Microorganisms live in complex communities in dynamic and constantly changing environments. In order to increase their fitness, microbes need to adapt to both the different environmental conditions and the presence of different competitive species. Communication between cells and between species has long been known to be central to the activation or suppression of key cellular metabolites, whereby individual cells can monitor group behavior and tailor transcriptional and translational activities accordingly. Based on this assumption, the interplay between strains of the same or different species has been used to enhance the production of known compounds and to discover new bioactive natural products [16; 41; 42; 43; 44; 45]. Among marine microorganisms, the co-cultivation approach has been shown to represent a promising strategy to discovery new bioactive compounds. For example, a new benzophenone antibiotic, called pestalone, that exhibits potent antibacterial activity against drug-resistant bacteria, was isolated from a mixed fermentation of a deuteromycete (_Pestalotia_ sp.) and an unidentified antibiotic-resistant marine bacterium [41]. Another successful example comes from the expression of the biosynthetic pathway for the production of four different diterpenoids, libertellenones A-D, which show varying levels of cytotoxicity against the HCT-116 human adenocarcinoma cell line. Libertellenones' production was obtained by culturing the marine fungus _Libertella_ sp. with a marine alpha-proteobacterium [46]. Similarly, the co-cultivation of two mangrove endophytic fungi led to the discovery of marinamides A and B [47], while [PERSON] and co-workers showed that mixed bacterial culture isolated from ocean floor sediments produced blue pigment with antibiotic activity [48]. The pigment was characterized as the phenazine derivative pyocyanin, and it was produced by a _Pseudomonas aeruginosa_ strains only when co-cultivated with a strain of _Enterobacter_ sp. Finally, the coral bacterium _Bacillus amyloliquefaciens_ GA40 stimulated production of lipopeptide antifungal metabolites when grown in the presence of _A. fumigatus_ and _A. niger_[49]. The strength of this approach has further been shown in one of the first systematic studies conducted to investigate the activation of cryptic or silent BGCs in the model fungus _A. nidulans_ during co-cultivation with different actinomycetes [44]. Among the tested actinomycetes, _S. rapamycinicus_ was found to selectively activate two silent gene clusters. One of the gene clusters produced the aromatic polyketide orsilic acid, lecanoric acid, and the cathepsin K inhibitors F-9775A/F-9775B. [PERSON] and colleagues conducted an interesting study on the effect of mycolic-acid containing bacteria on the production of secondary metabolites by actinomycetes strains [43]. They could show that _Tsukamurella pulmonis_ enhances the production of known metabolites in 54.5% of the tested actinomycetes strains and triggers the production of unknown compounds in 36.6% on the strains.  
Although applicable only to cultivable microorganisms, the co-cultivation approaches represent a solid and promising strategy to discovery new bioactive metabolites. In this respect, the recent effort in the isolation of new marine microorganisms for the discovery of unknown secondary metabolites offers an invaluable platform to explore multiple cultivation conditions, external cues, and co-cultivation possibilities, capitalizing on the vast diversity hidden onto the marine environments (Table 1). While the underlying factors responsible for activation of silent BGCs during co-cultivation are likely to be species and combination specific, the signaling systems described in the following sections are likely to play some role.