Honaucins A−C, Potent Inhibitors of Inflammation and Bacterial Quorum Sensing: Synthetic Derivatives and Structure-Activity Relationships

Abstract

SUMMARY Honaucins A–C were isolated from the cyanobacterium Leptolyngbya crossbyana which was found overgrowing corals on the Hawaiian coast. Honaucin A consists of (S)-3-hydroxy-γ-butyrolactone and 4-chlorocrotonic acid which are connected via an ester linkage. Honaucin A and its two natural analogs exhibit potent inhibition of bioluminescence, a quorum sensing-dependent phenotype, in Vibrio harveyi BB120 as well as of lipopolysaccharide-stimulated nitric oxide production in the murine macrophage cell line RAW264.7. The decrease in nitric oxide production was accompanied by a decrease in the transcripts of several pro-inflammatory cytokines, most dramatically interleukin-1β. Synthesis of honaucin A as well as a number of analogs and subsequent evaluation in anti-inflammation and quorum sensing inhibition bioassays revealed the essential structural features for activity in this chemical class, and provided analogs with greater potency in both assays.

Modular Strategies for Structure and Function Employed by Marine Cyanobacteria: Characterization and Synthesis of Pitinoic Acids

“…One of the common biological roles of fatty acid compounds produced by bacteria in large quantities is the interference with quorum sensing (communication between bacteria in response to high population densities). This was shown in several previous reports, [17][18][19][20] including by our group where we reported the anti-quorum sensing activity of lyngbyoic acid. 21 In Pseudomonas aeruginosa, quorum sensing (QS) system integrates two chemically distinct classes of signal molecules which act on differnet QS pathways, the Nacylhomoserine lactones which act on the LasR-LasI pathway, and the 4-quinolones which act on the Pseudomonas quinolone signaling pathway.…”

“…This notion is consistent with the structural similarity of this moiety to other previously reported anti-inflammatory compounds and to the anti-inflammatory acid part in honaucins. 20 Additionally, using 1 H NMR and MS analysis, we were able to confirm the presence of this -hydroxy acid in one of the minor impure HPLC fractions obtained during the purification of 2 (Supp. Fig.…”

“…Similar structural features were also present in the recently reported anti-inflammatory marine cyanobacterial fatty acid esters honaucins, which also contain a terminal chloride. 20 We initiated the biological characterization of 2 by testing its effect on LPS-induced inflammatory responses in human acute monocytic leukemia cell line THP-1 after differentiation to macrophages. Compound 2 was able to decrease the transcript levels of the pro-inflammatory cytokines TNF-and IL-6 after 4 h of LPS stimulation at 100 M (Figure 2).…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…Secondary metabolites isolated and purified from sponges (290) and Gram-negative cyanobacteria (296) also exemplify successes where low-micromolar concentrations of purified compounds could inhibit QS reporters. Recently, for example, low-molecularweight compounds isolated from the marine cyanobacterium Leptolyngbya and named honaucins A to C (for Honaunau Bay, HI, the location of the reef where the bacteria were isolated) (Table 3) exhibited potent, low-micromolar QSI activity in both a V. harveyi bioluminescence assay and an E. coli AHL reporter assay (140). Halogenated derivatives of these compounds, however, showed impressive submicromolar activity.…”

Estudo químico de cianobactérias marinhas e do cultivo misto entre a linhagem Geitlerinema sp CENA556 e o fungo Trichoderma atroviride, endófito da alga marinha Bostrychia tenella

“…Estes podem viver de forma livre ou em associação com hospedeiros como animais marinhos e plantas NUNNERY et al;CHLIPALA et al, 2011;DUCAT et al, 2011;COSTA et al, 2012). Dentre as bioatividades descritas para estes metabólitos podemos citar a citotóxica, antitumoral, antiviral, antibacteriana, antiprotozoal, antifúngica, algicida, antiinflamatória, inibidora enzimática, antiobesidade, canabinomimética e protetora contra radiação ultravioleta (BLUNT et al, 2016;DITTMANN et al, 2015;NIEDERMEYER, 2015;RASTOGI et al, 2015;SWAIN et al, 2015;PEREIRA et al, 2010;TAN, 2010;CHOI et al, 2012a;CHOI et al, 2012b;DABAS et al, 2014 Afora o enfoque farmacológico, a engenharia metabólica de cianobactérias também tem sido aplicada com sucesso para a obtenção de produtos biotecnológicos. Desta forma, a capacidade fotossintética das cianobactérias tem sido direcionada para a produção de biocombustíveis, bioplásticos e outras commodities químicas (GAO et al, 2016;HEIMANN, 2016;ANGERMAYR et al, 2015).…”