With 70% of the Earth’s surface covered in water, the marine ecosystem offers immense opportunities for drug discovery and development. Due to the decreasing rate of novel natural product discovery from terrestrial sources in recent years, many researchers are beginning to look seaward for breakthroughs in new therapeutic agents. As part of an ongoing marine drug discovery programme in Singapore, an integrated approach of combining metabolomic and genomic techniques were initiated for uncovering novel anti-quorum sensing molecules from bacteria associated with subtidal samples collected in the Singapore Strait. Based on the culture-dependent method, a total of 102 marine bacteria strains were isolated and the identities of selected strains were established based on their 16S rRNA gene sequences. About 5% of the marine bacterial organic extracts showed quorum sensing inhibitory (QSI) activity in a dose-dependent manner based on the Pseudomonas aeruginosa QS reporter system. In addition, the extracts were subjected to mass spectrometry-based molecular networking and the genome of selected strains were analysed for known as well as new biosynthetic gene clusters. This study revealed that using integrated techniques, coupled with biological assays, can provide an effective and rapid prioritization of marine bacterial strains for downstream large-scale culturing for the purpose of isolation and structural elucidation of novel bioactive compounds.

Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. Cancer Res; 77(16); 4342–54. ©2017 AACR.

Benderamide A (1), a (S)-2,2-dimethyl-3-hydroxy-7-octynoic acid (S-Dhoya)-containing cyclic depsipeptide that belongs to the kulolide superfamily, was isolated from a Singapore collection of cf. Lyngbya sp. marine cyanobacterium using a bioassay-guided approach. While the planar structure of 1 was elucidated using a combination of 1D and 2D NMR experiments and MS analysis, the absolute configuration was subsequently achieved using the results obtained from Marfey’s analysis, comparative analysis of nuclear overhauser effect spectroscopy (NOESY) with the known compound 3, and one dimensional-nuclear overhauser effect (1D-NOE). Although 1 did not display antiproliferative activity against MCF7 breast cancer cells, the presence of an Ala instead of Gly suggests a possible mechanistic pathway to explain the consequential decrease in cytotoxicity compared to the closely related 2. In addition, results obtained from an LC–MS/MS-based molecular networking algorithm revealed two other closely related compounds encouraging further identification and isolation from the same marine cyanobacterium extract.