## 2 Environmental Cues and Co-Cultivation
### Microbial Signaling and Cryptic Clusters  
Another class of compound that has been shown to elicit activation of BGCs is the quorum sensing class of signaling molecule. A key control mechanism for cellular physiology, virulence and antibiotic production, quorum sensing molecules are widespread among microbial organisms. The nature and chemical composition of these signal molecules can be quite diverse, with the paradigm class of signal \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Organism** & **Compound** & **Technique** & **Ref.** \\ \hline _A. ochraceus_ (DSM-7428) & Aspinolides and Aspinonene/ & Alteration of & \\  & Aspyrone co-metabolites & cultivation conditions & [50] \\ \hline _Streptomyces_ sp. strain C34 & Chaxalactins A–C & Alteration of & \\  & & cultivation conditions & [27] \\ \hline _Paraphaeosphaeria quadrisepata_ & Cytosporones F–I; Quadriseptin A; & & \\  & 5’-Hydroxymonocillin III; Monocillin I & Alteration of & \\  & and III; Aposphaerin B & cultivation conditions & [28] \\ \hline _Phomopsis asparagi_ & Chaetologbosin-510, -540, and -542 & External cues & [33] \\ \hline _Pestalotia_ sp. & Pestalone & Co-culture & [41] \\ \hline _Libertella_ sp. & Libertellenones A–D & Co-culture & [46] \\ \hline Uncharacterized endophytic fungi & Marinamide A–B & Co-culture & [47] \\ \hline _Pectobacterium carotooverum_ & Orange pigment & Quorum-sensing & [51] \\ \hline _B. cepacia_ & Enacyloxin lia iso-enacyloxin lia & Quorum-sensing & [52] \\ \hline _B. thailandensis_ & Novel thailandamide lactone variant & Mutation in & \\  & & transcription factor & [53, 54] \\ \hline _Streptomyces_ sp. & Angucyclinone & Mutation in & \\  & & transcription factor & [55, 56] \\ \hline _S. coelicolor_ & Uncharacterized antibacterial & Mutation in & \\  & compound and pigment & transcription factor & [57] \\ \hline _S. orinoci_ & Spectinabilin & Artificial promoters & [58] \\ \hline _Saccharomyces_ sp. CNQ-490 & Taromycin A & Artificial promoters & [4] \\ \hline _A. nidulans_ & Emodin, monodictyphenone, and & & \\  & F9775A/F9775B & Epigenetic mining & [59] \\ \hline _S. lividans_ & Blue-pigmented antibiotic actinorhodin & Ribosomal & [60] \\  & & Engineering & [60] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Methods and outcomes for activation of cryptic clusters. for Gram negative organisms being the acyl-homoserine lactone (AHL) class [61]. First discovered in the marine symbiont _Vibrio fischeri_, AHL signaling systems have been identified in several marine organisms, suggesting a role in population dynamics within this ecosystem [62, 63, 64, 65]. However, the nature of cell-cell signaling in marine sponges and other marine niches remains less well understood. Nevertheless, this signal based mechanism for control of cellular behavior has already been shown to coordinate antibiotic biosynthesis within producing bacteria, as seen with pyrrolirin production in a rhizospheric biocontrol strain of _Serratia plymuthica_[66], and with production of a polyketide antibiotic in _B. thailandensis_[67]. The quorum sensing controlled Evr transcriptional regulator was shown to activate a conserved cryptic pigment biosynthetic cluster and a novel phenomycin-like locus in the plant pathogen _Pectobacterium carootovorum_[51]. Intriguingly, synthase genes encoding AHL signal molecules have been identified adjacent to BGCs, e.g., indolmycin production in _Pseudoalteromonas luteeviolacea_[68], raising the possibility of a direct role in the activation of these BGCs [69]. Enacyloxin IIa and its stereoisomer designated iso-enacyloxin IIa were identified as metabolic products of a QS modulated cryptic gene cluster in _B. cepacia_ complex (Bcc) isolates, in this case encoded in a genomic island [52]. The biosynthesis of carbapenem antibiotic and prodigiosin pigment in _Serratia_ is also under quorum sensing control, a feature that has been used for the development of biosensors for QS production and interference [70].