Bioactive Potential of Extracts of <i>Labrenzia aggregata</i> Strain USBA 371, a Halophilic Bacterium Isolated from a Terrestrial Source

Previous studies revealed the potential of <i>Labrenzia aggregata</i> USBA 371 to produce cytotoxic metabolites. This study explores its metabolic diversity and compounds involved in its cytotoxic activity. Extracts from the extracellular fraction of strain USBA 371 showed high levels of cytotoxic activity associated with the production of diketopiperazines (DKPs). We purified two compounds and a mixture of two other compounds from this fraction. Their structures were characterized by 1D and 2D nuclear magnetic resonance (NMR). The purified compounds were evaluated for additional cytotoxic activities. Compound <b>1</b> (cyclo (<span style="font-variant: small-caps;">l</span>-Pro-<span style="font-variant: small-caps;">l</span>-Tyr)) showed cytotoxicity to the following cancer cell lines: breast cancer 4T1 (IC₅₀ 57.09 ± 2.11 µM), 4T1H17 (IC₅₀ 40.38 ± 1.94), MCF-7 (IC₅₀ 87.74 ± 2.32 µM), murine melanoma B16 (IC₅₀ 80.87 ± 3.67), human uterus sarcoma MES-SA/Dx5 P-pg (−) (IC₅₀ 291.32 ± 5.64) and MES-SA/Dx5 P-pg (+) (IC₅₀ 225.28 ± 1.23), and murine colon MCA 38 (IC₅₀ 29.85 ± 1.55). In order to elucidate the biosynthetic route of the production of DKPs and other secondary metabolites, we sequenced the genome of <i>L. aggregata</i> USBA 371. We found no evidence for biosynthetic pathways associated with cyclodipeptide synthases (CDPSs) or non-ribosomal peptides (NRPS), but based on proteogenomic analysis we suggest that they are produced by proteolytic enzymes. This is the first report in which the cytotoxic effect of cyclo (<span style="font-variant: small-caps;">l</span>-Pro-<span style="font-variant: small-caps;">l</span>-Tyr) produced by an organism of the genus <i>Labrenzia</i> has been evaluated against several cancer cell lines.