**4. Conclusions**

Marine-derived bacteria, particularly those isolated in association with marine invertebrates, such as sponges, have been shown to be reservoirs of bioactive molecules, including those with antibacterial, antifungal, and anticancer activities. Among these newly identified bioactive compounds, the surugamides and their derivatives are of particular interest due to their clinically relevant bioactivities, i.e., anticancer and antifungal, and their original metabolic pathway.

Based on genome mining, this study identified the previously unreported capability of the marine sponge-derived isolate *Streptomyces* sp. SM17 to produce surugamide A and also sheds new light on factors such as the carbon catabolite repression (CCR) that may be involved in regulating production of this molecule. Phylogenomics analysis indicated that the *sur* BGC is commonly present in members of the proposed *albidoflavus* phylogroup, and that the *sur* BGCs present in different isolates derived from varied environmental niches may possess a common ancestry. Although high quality genomic data from this proposed *albidoflavus* phylogroup are still lacking, results presented here suggest that the *sur* BGCs derived from *Streptomyces* isolated from aquatic saline environment are more similar to each other, when compared to those isolated from terrestrial environments.

Chemical analysis was performed in order to assess differential production of surugamide A when comparing a marine *Streptomyces* isolate with a terrestrial *Streptomyces* isolate, namely SM17 and J1074 strains, respectively, following an OSMAC-based approach employing different culture media. This analysis showed that not only the marine-derived isolate SM17 was capable of producing more surugamide A when compared to J1074 under all the conditions tested, but also that the biosynthesis of surugamide A is likely to be influenced by the CCR, and potentially by the presence of salts in the growth medium. These results also highlight the importance of employing an OSMAC-based approach even when analysing the production of known compounds, since there is a clear difference in the yields of surugamide A obtained when employing different culture media. Thus, it is possible to gain further insights into the production of bacterial types of compounds by 1) discovering strains that possess a higher capability to produce these compounds; 2) establishing optimal conditions for the biosynthesis of their production; and 3) providing a better understanding of the genetic and regulatory mechanisms potentially underpinning the production of these compounds.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2076-2607/7/10/394/s1, Figure S1: Groups of orthologous genes in the genomes of the *albidoflavus* phylogroup, Figure S2: Calibration curve for surugamide A, Table S1: Genome statistics of the *albidoflavus* phylogroup.

**Author Contributions:** Conceived and designed the experiments: E.L.A., A.F.C.R, O.P.T, A.D.W.D. Performed the experiments: E.L.A., A.F.C.R., N.K., L.K.J. Analysed the data: E.L.A., A.F.C.R., N.K., L.K.J., O.P.T., S.A.J., A.D.W.D. Wrote the paper: E.L.A., O.P.T., A.D.W.D.

**Funding:** E.L.A. acknowledges the funding support of the Brazilian National Council for Scientific and Technological Development (CNPq). This project was supported by a research grant from the Marine Institute through the NMBLI project (Grant-Aid Agreement PBA/MB/16/01) and by the Marine Biotechnology ERA/NET, NEPTUNA project (contract No. PBA/MB/15/02) and by Science Foundation Ireland (SSPC-2, 12/RC/2275).

**Conflicts of Interest:** The authors declare no conflict of interest.
