Mar.Drugs 2014,12 1069 discovery [28].The two techniques together make the screening of synthetic compounds faster and cheaper as compared to traditional natural product discovery 9.Nevertheess,such rapid synthetic techniques have not led to successful development of bioactives.For instance,early CC libraries were composed of compounds with poor solubility,low purity and short chemical diversity and hence only a few useful hits were identified [28.29].So,some companies,driven by achievements on total or hemi-synthesis of NP [291.development of synthetic analogues or design of synthesizable pharmacophores of reduced complexity.brought back natural product discovery programs [30.31]. The development of refined analytical and spectroscopic methods.particularly high resolution nuclear magnetic resonance(NMR)and mass spectrometry (MS)has also contributed tremendously to put NP,and in particular MNP,back on the track of drug discovery [32].In fact,the many advances in spectroscopic methods.allowed the de novo structure determination of new chemical entities (NCEs) in very small concentrations [33]even in complex mixtures as crude extracts. An additional fact that helped to put MNP back on the agenda of drug discovery programs was the recent development of techniques that allow the access to a vast community of microbial sources unattainable until recently.Culture broths of new microorganisms are now very easy to obtain,through small scale,high-throughput cultivation methods that use nutrient deficient media,specific nutrients and long cultivation times [34].In addition,as more than 99%of the microorganisms is not readily cultivable,culture independent methods based on the total DNA of the bacterial community,can now detect a considerable fraction of the uncultivable organisms (in addition to those that can be cultured) enabling the access to these previously unreachable natural product resources.Metagenomics,in particular.enables direct access to the genomes of whole environmental uncultivable microorganisms by total environmental dna extraction 1351 and it has already proven to be a good alternative for exploiting uncultivable microorganisms for natural product discovery 36]. Ultimately,genome mining.which consists in the analyses of genome sequences for the identification of genes encoding proteins,is an additional recent approach which has allowed the discovery of numerous novel NP and also revealed gene clusters and novel pathways for the biosynthesis of several known natural compounds [37].The biosynthesis of polyketides,for example,has attracted most attention,since many commercial antibiotics derive from this pathway.Genome mining is of high importance on NP discovery as it opens up the possibility of expressing the gene clusters in a heterologous organism. obtaining the desired secondary metabolites [38].Furthermore,it has also allowed the development of combinatorial biosynthesis,which involves the genetic manipulation of the gene cluster involved in NP biosynthesis to obtain new molecules that would be difficult to synthesize using other methods [39]. All the progressive improvements in the past 50 years of exploration of the marine enviro pointed out earlier,have resulted in the isolation of approximately 20,000 structurally unique bioactive MNP [40].Just in 2012,1241 new compounds were reported which clearly identifies the marine environment as a rich source of bioactive molecules [Nevertheless,despite this enormous numbe of structurally unique bioactive MNP.to the date the global marine pharmaceutical pipeline includes only eight approved drugs,twelve NP(or derivatives thereof)in different clinical phases and a large number of marine chemicals in the preclinical phase [6,41,42].The global market for marine-derived drugs is forecasted to reach $8.6 B by 2016 [43]. In alignment with the pharmaceutical industry,the the sea in the search for new molecules.In fact,MNP are on high demand for skin care,as theyMar. Drugs 2014, 12 1069 discovery [28]. The two techniques together make the screening of synthetic compounds faster and cheaper as compared to traditional natural product discovery [29]. Nevertheless, such rapid synthetic techniques have not led to successful development of bioactives. For instance, early CC libraries were composed of compounds with poor solubility, low purity and short chemical diversity and hence only a few useful hits were identified [28,29]. So, some companies, driven by achievements on total or hemi-synthesis of NP [29], development of synthetic analogues or design of synthesizable pharmacophores of reduced complexity, brought back natural product discovery programs [30,31]. The development of refined analytical and spectroscopic methods, particularly high resolution nuclear magnetic resonance (NMR) and mass spectrometry (MS) has also contributed tremendously to put NP, and in particular MNP, back on the track of drug discovery [32]. In fact, the many advances in spectroscopic methods, allowed the de novo structure determination of new chemical entities (NCEs) in very small concentrations [33] even in complex mixtures as crude extracts. An additional fact that helped to put MNP back on the agenda of drug discovery programs was the recent development of techniques that allow the access to a vast community of microbial sources unattainable until recently. Culture broths of new microorganisms are now very easy to obtain, through small scale, high-throughput cultivation methods that use nutrient deficient media, specific nutrients and long cultivation times [34]. In addition, as more than 99% of the microorganisms is not readily cultivable, culture independent methods based on the total DNA of the bacterial community, can now detect a considerable fraction of the uncultivable organisms (in addition to those that can be cultured) enabling the access to these previously unreachable natural product resources. Metagenomics, in particular, enables direct access to the genomes of whole environmental uncultivable microorganisms by total environmental DNA extraction [35] and it has already proven to be a good alternative for exploiting uncultivable microorganisms for natural product discovery [36]. Ultimately, genome mining, which consists in the analyses of genome sequences for the identification of genes encoding proteins, is an additional recent approach which has allowed the discovery of numerous novel NP and also revealed gene clusters and novel pathways for the biosynthesis of several known natural compounds [37]. The biosynthesis of polyketides, for example, has attracted most attention, since many commercial antibiotics derive from this pathway. Genome mining is of high importance on NP discovery as it opens up the possibility of expressing the gene clusters in a heterologous organism, obtaining the desired secondary metabolites [38]. Furthermore, it has also allowed the development of combinatorial biosynthesis, which involves the genetic manipulation of the gene cluster involved in NP biosynthesis to obtain new molecules that would be difficult to synthesize using other methods [39]. All the progressive improvements in the past 50 years of exploration of the marine environment, pointed out earlier, have resulted in the isolation of approximately 20,000 structurally unique bioactive MNP [40]. Just in 2012, 1241 new compounds were reported which clearly identifies the marine environment as a rich source of bioactive molecules [8]. Nevertheless, despite this enormous number of structurally unique bioactive MNP, to the date the global marine pharmaceutical pipeline includes only eight approved drugs, twelve NP (or derivatives thereof) in different clinical phases and a large number of marine chemicals in the preclinical phase [6,41,42]. The global market for marine-derived drugs is forecasted to reach $8.6 B by 2016 [43]. In alignment with the pharmaceutical industry, the cosmeceutical industry is increasingly turning to the sea in the search for new molecules. In fact, MNP are on high demand for skin care, as they