Inhibition of Quorum Sensing System in Pseudomonas aeruginosa by Psammaplin A and Bisaprasin Isolated from the Marine Sponge Aplysinella rhax

Natural products isolated from marine sponges have exhibited profound bioactivity and, in some cases, serve as potent quorum sensing inhibitory agents by preventing microbial biofilm formation. In this study, the inhibitory potential of the psammaplin type compounds, psammaplin A (1) and bisaprasin (2), isolated from the marine sponge, Aplysinella rhax, was evaluated in the quorum-sensing inhibitory assay based on the Pseudomonas aeruginosa PAO1 lasB-gfp and P. aeruginosa PAO1 rhlA-gfp biosensor strains. The result indicated that psammaplin A (1) showed moderate inhibition against lasB-gfp biosensor strains but significantly inhibited the QS-gene promoters, rhlA-gfp with IC50 value at 30.69 and 2.64 μM, respectively. In contrast, bisaprasin (2) displayed significant inhibition for both biosensor strains, lasB-gfp and rhlA-gfp with IC50 values at 8.70 and 8.53 μM, respectively. To our knowledge, the antiquorum sensing activity of these marine-derived bromotyrosine compounds is described here for the first time.Significance and Impact of the StudyThe attention of the scientific community has been drawn to using marine sources to find novel quorum sensing inhibitors as antipathogenic drugs to combat antimicrobial resistance and pathogenesis caused by the proliferation of pathogenic bacteria mediated by the quorum sensing (QS) system. By blocking the QS signalling communication, the ability to assemble an organised community structure that enables drug resistance and production of virulence factors will be attenuated. The significance of this investigation is based on the discovery of bromotyrosine derivatives as potential new drug leads for the development of antipathogenic agents.

Marine-Derived Natural Lead Compound Disulfide-Linked Dimer Psammaplin A: Biological Activity and Structural Modification

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug Administration. Numerous bromotyrosine derivatives have been isolated as a type of marine natural products. Among them, psammaplin A, including the oxime groups and carbon–sulfur bonds, was the first identified symmetrical bromotyrosine-derived disulfide dimer. It has been found to have a broad bioactive spectrum, especially in terms of antimicrobial and antiproliferative activities. The highest potential indole-derived psammaplin A derivative, UVI5008, is used as an epigenetic modulator with multiple enzyme inhibitory activities. Inspired by these reasons, psammaplin A has gradually become a research focus for pharmacologists and chemists. To the best of our knowledge, there is no systematic review about the biological activity and structural modification of psammaplin A. In this review, the pharmacological effects, total synthesis, and synthesized derivatives of psammaplin A are summarized.

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.