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

Choi, Hyukjae; Mascuch, Samantha J.; Villa, Francisco A.; Byrum, Tara; Teasdale, Margaret E.; Smith, Jennifer E.; Preskitt, Linda B.; Rowley, David C.; Gerwick, Lena; Gerwick, William H.

doi:10.1016/j.chembiol.2012.03.014

Cited by 101 publications

(100 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.…”

supporting

confidence: 83%

“…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.…”

mentioning

confidence: 84%

“…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).…”

Section: Nih Public Accessmentioning

confidence: 99%

See 2 more Smart Citations

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

Montaser¹,

Paul²,

Luesch³

2013

Planta Med

View full text Add to dashboard Cite

Novel bioactive lipids were identified from a Guamanian cyanobacterium; the Pseudomonas aeruginosa quorum sensing inhibitor pitinoic acid A (1) and the anti-inflammatory pitinoic acids B (2) and C. The structure of 2 was confirmed by synthesis, which also allowed for biological evaluation. Since 2 is an ester of pitinoic acids A and C, it represents a prodrug strategy to liberate dual biological activity for the management of P. aeruginosa infections and their associated inflammation.Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in different host tissues and organs. For example, cystic fibrosis (CF) infections and microbial keratitis (MK) are two of the most serious lung and eye infections, respectively, caused by this organism. 1, 2 Bacterial quorum sensing (QS) has been shown to play a major role in bacterial pathogenesis, where the infection and tissue destruction are facilitated by several QS-regulated virulence factors including elastase (LasB) and the pigment pyocyanin. 2,3 Tissue damage is also aggravated by the host's defense response, where the release of pro-inflammatory mediators and the prolonged inflammatory response are other contributors to tissue pathology. 2, 4-8 Accordingly, inhibiting QS pathways in P. aeruginosa and simultaneously controlling the associated inflammatory response is a promising strategy for the treatment of infections caused by this organism.luesch@cop.ufl.edu. Supporting Information Available. 1D and 2D NMR spectra for compounds 1 and 2, supporting figures including spectral data and characterization of synthetic intermediates, experimental procedures and additional RT-qPCR data. This material is available free of charge via the Internet at http://pubs.acs.org. During our efforts to discover novel bioactive compounds from marine cyanobacteria, we explored a population of a marine cyanobacterium morphologically similar to Lyngbya sp. NIH Public Accesscollected from a channel at the north end of Piti Bay at Guam, through NMR-guided fractionation. We isolated and characterized the novel lipids pitinoic acid A (1) (5-methylene decanoic acid) and its chlorinated ester, pitinoic acid B (2). The fatty acid 1 inhibits QS in P. aeruginosa, while the ester 2 prevents the induction of pro-inflammatory cytokine expression in LPS-induced THP-1 macrophages. In addition, we were able to identify the presence of pitinoic acid C, the alcohol moiety in 2, in one HPLC-fraction, which also maintained the anti-inflammatory effect detected for 2. Based on this, 2 appears to be a nature-designed prodrug which could deliver two essential moieties with different bioactivities upon hydrolysis; the QS-inhibitory module pitinoic acid A (1) and the antiinflammatory module pitinoic acid C.The EtOAc-MeOH extract was subjected to solvent-solvent partitioning followed by fractionation using silica gel chromatography. 1 H NMR profiles of the generated silica fractions showed a major simple fatty acid (1) HPLC purification of another silica fraction that elut...

show abstract

supporting

confidence: 83%

mentioning

confidence: 84%

Section: Nih Public Accessmentioning

confidence: 99%

See 1 more Smart Citation

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

Montaser¹,

Paul²,

Luesch³

2013

Planta Med

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Natural-product Qs Inhibitorsmentioning

confidence: 99%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

690

556

View full text Add to dashboard Cite

SUMMARY Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

show abstract

“…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).…”

Section: Microrganismos Marinhos Como Fonte Inestimável De Novos Produnclassified

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

Silva¹

View full text Add to dashboard Cite

Estudo químico de cianobactérias marinhas e do cultivo misto entre a linhagem Geitlerinema sp CENA556 e o fungoMarine organisms are recognized as a rich reservoir of natural products with exceptional molecular structures. In this context, cyanobacteria and endophytic fungi has emerged as source of promising bioactive compounds. The aim of this work was to look for biologically active compounds from the marine cyanobacteria strains, collected in Ubatuba, coast of the São Paulo state (Brazil), and to explore the biosynthetic potential of the fungus Trichoderma atroviride (endophyte isolated from marine seaweed Bostrychia tenella, collected in the rocky Shore of Praia de Fortaleza, Ubatuba, SP) by coculture with the cyanobacteria strain Geitlerinema sp CENA556. Initially, five species of marine cyanobacteria were isolated from the sample collected at the coast of São Paulo, and then characterized phylogenetically. Among them, the strains coded as Geitlerinema sp CENA552 and Geitlerinema sp CENA556 were cultured in mimicking seawater medium and extracted with a mix of CH 2 Cl 2 / MeOH (2:1), and then EtOAc. The concentrated extract was partitioned into hexane fraction and MeOH/H2O (95: 5) fraction. Four known compounds were identified from the hexane fraction of the Geitlerinema sp CENA552 extract by GC-MS analysis: 2-hexyl-1-decanol, 3-octadecene, neophytadiene, and methyl palmitate. Similarly, the compounds dodecanal, 8-heptadecene, palmitaldehyde, neophytadiene, phytol, methyl palmitoleate, methyl 7-hexadecenoate, and methyl 9-hexadecenoate were identified from the hexane fraction of the Geitlerinema sp CENA556 extract. Starting of MeOH/H2O (95: 5) fraction of Geitlerinema sp CENA556 extract, seven compounds were isolated by semi preparative HPLC-PDA and identified by NMR spectroscopy and HR-MS analysis. Among them, five known nucleosides first isolated from cyanobacteria: 2'-deoxyuridine, thymidine, adenosine, 2'-deoxyadenosine, and uridine. Also two amino acids: D-leucine and L-phenylalanine. Trichoderma atroviride was grown alone in rice and Czapeck media and the coculture between the fungus and the cyanobacteria (Geitlerinema sp CENA556) were performed using the same media. The CH 2 Cl 2 / MeOH (2:1) and EtOAc pooled extract from the coculture of the fungus T. atroviride and the cyanobacteria Gleiterinema sp CENA556 in Czapek medium shows significant difference in the metabolites production when compared to individually cultured fungus and cyanobacteria. Four catechol type siderophores were isolated from MeOH/H2O (95: 5) fraction of this extract: agrobactin, agrobactin A, photobactin and one novel compound. Agrobactin, the major compound, showed substantial antibacterial activity against P. mirabilis, E. coli, S. saprophyticus, S. aureus and P. aeruginosa. Thus, the studied brazilian cyanobacteria Geitlerinema sp appeared to be promising for isolation of nucleosides with biological activity. Furthermore, the fungus T. atroviride proved to be a prolific source of antibacterial siderophores obtained by biologic...

show abstract

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

Cited by 101 publications

References 50 publications

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

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

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

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

Contact Info

Product

Resources

About