Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

Rabe, Patrick; Klapschinski, Tim A.; Brock, Nelson L.; Citron, Christian A.; D’Alvise, Paul; Gram, Lone; Dickschat, Jeroen S.

doi:10.3762/bjoc.10.188

Cited by 12 publications

(12 citation statements)

References 21 publications

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“…As the search for new antibiotics continues, TDA produced by marine sponge isolates has potential as a platform molecule for clinical development. Indeed, synthetic modification of the TDA framework resulting in analogues with enhanced antimicrobial activity has recently been reported [ 57 ], evidence that chemical modification of the compound can be achieved. Furthermore, initial toxicity studies have revealed that TDA is non-toxic in two eukaryotic models [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Characterisation of Non-Autoinducing Tropodithietic Acid (TDA) Production from Marine Sponge Pseudovibrio Species

et al. 2014

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The search for new antimicrobial compounds has gained added momentum in recent years, paralleled by the exponential rise in resistance to most known classes of current antibiotics. While modifications of existing drugs have brought some limited clinical success, there remains a critical need for new classes of antimicrobial compound to which key clinical pathogens will be naive. This has provided the context and impetus to marine biodiscovery programmes that seek to isolate and characterize new activities from the aquatic ecosystem. One new antibiotic to emerge from these initiatives is the antibacterial compound tropodithietic acid (TDA). The aim of this study was to provide insight into the bioactivity of and the factors governing the production of TDA in marine Pseudovibrio isolates from a collection of marine sponges. The TDA produced by these Pseudovibrio isolates exhibited potent antimicrobial activity against a broad spectrum of clinical pathogens, while TDA tolerance was frequent in non-TDA producing marine isolates. Comparative genomics analysis suggested a high degree of conservation among the tda biosynthetic clusters while expression studies revealed coordinated regulation of TDA synthesis upon transition from log to stationary phase growth, which was not induced by TDA itself or by the presence of the C10-acyl homoserine lactone quorum sensing signal molecule.

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Section: Discussionmentioning

confidence: 99%

Characterisation of Non-Autoinducing Tropodithietic Acid (TDA) Production from Marine Sponge Pseudovibrio Species

et al. 2014

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“…Members of this group have also been repeatedly detected in aquaculture systems (Hjelm et al, 2004b;Porsby et al, 2008). Some species, including Phaeobacter inhibens and Ruegeria mobilis, produce the potent antibacterial compound tropodithietic acid (TDA) (Bruhn et al, 2005;Porsby et al, 2008), which is active against a range of Gram-positive and Gram-negative bacteria (Kintaka et al, 1984;Porsby et al, 2011;Rabe et al, 2014). TDA has low toxicity to the roundworm Caenorhabditis elegans (Neu et al, 2014), which is often used as a model organism for testing cytotoxicity (Sese et al, 2009;Sprando et al, 2009) resembling the effects induced in mammalian model organisms (Sprando et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Tropodithietic acid induces oxidative stress response, cell envelope biogenesis and iron uptake in Vibrio vulnificus

Dittmann

Porsby

Gonçalves

et al. 2019

Environ Microbiol Rep

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Summary The Roseobacter group is a widespread marine bacterial group, of which some species produce the broad‐spectrum antibiotic tropodithietic acid (TDA). A mode of action for TDA has previously been proposed in Escherichia coli, but little is known about its effect on non‐producing marine bacteria at in situ concentrations. The purpose of this study was to investigate how a sub‐lethal level of TDA affects Vibrio vulnificus at different time points (30 and 60 min) using a transcriptomic approach. Exposure to TDA for as little as 30 min resulted in the differential expression of genes associated with cell regeneration, including the up‐regulation of those involved in biogenesis of the cell envelope. Defence mechanisms including oxidative stress defence proteins and iron uptake systems were also up‐regulated in response to TDA, while motility‐related genes were down‐regulated. Gene expression data and scanning electron microscopy imaging revealed a switch to a biofilm phenotype in the presence of TDA. Our study shows that a low concentration of this antibiotic triggers a defence response to reactive oxygen species and iron depletion in V. vulnificus, which indicates that the mode of action of TDA is likely more complex in this bacterium than what is known for E. coli.

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“…In contrast, V. parahaemolyticus was more tolerant toward 15 with an MIC of 15.6 μM. [72] Other studies reported MICs of 15.6 μM [69] and 14 μM [67] /19 μM [70] for V. vulnificus CMCP6 and the fish pathogen V. anguillarum 90-11-287, respectively. Low MICs of 2.3 μM were also determined for the coral pathogens V. coralliilyticus and V. owensii.…”

Section: Minimum Inhibitory Concentration Of Tropodithietic Acid Agaimentioning

confidence: 99%

“…Typhimurium, Enterobacter cloacea, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and Gram-positive bacteria (e. g., Staphylococcus aureus (MSSA and MRSA), Enterococcus faecalis, Listeria monocytogenes, Bacillus subtilis). Typically, MICs ranged between 14 and 118 μM for 15 [67,70] and 7.4-118 μM for thiotropocin at pH 7. Notably, MIC values for thiotropocin were much lower at pH 9 and drastically higher at pH 5.…”

Section: Minimum Inhibitory Concentration Of Tropodithietic Acid Agaimentioning

confidence: 99%

“…[66] Interestingly, structure-activity relationship studies using chemically synthesized analogues of 15 including halogenated derivatives showed that 15 was generally the most potent antibiotic when tested against S. aureus and V. anguillarum 90-11-287. [70] Figure 11. Proposed MoA of 15 and (self)resistance mechanism (figure modified after Wilson et al).…”

Section: Minimum Inhibitory Concentration Of Tropodithietic Acid Agaimentioning

confidence: 99%

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Bacterial Tropone Natural Products and Derivatives: Overview of their Biosynthesis, Bioactivities, Ecological Role and Biotechnological Potential

et al. 2020

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Tropone natural products are non‐benzene aromatic compounds of significant ecological and pharmaceutical interest. Herein, we highlight current knowledge on bacterial tropones and their derivatives such as tropolones, tropodithietic acid, and roseobacticides. Their unusual biosynthesis depends on a universal CoA‐bound precursor featuring a seven‐membered carbon ring as backbone, which is generated by a side reaction of the phenylacetic acid catabolic pathway. Enzymes encoded by separate gene clusters then further modify this key intermediate by oxidation, CoA‐release, or incorporation of sulfur among other reactions. Tropones play important roles in the terrestrial and marine environment where they act as antibiotics, algaecides, or quorum sensing signals, while their bacterial producers are often involved in symbiotic interactions with plants and marine invertebrates (e. g., algae, corals, sponges, or mollusks). Because of their potent bioactivities and of slowly developing bacterial resistance, tropones and their derivatives hold great promise for biomedical or biotechnological applications, for instance as antibiotics in (shell)fish aquaculture.

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Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

Cited by 12 publications

References 21 publications

Characterisation of Non-Autoinducing Tropodithietic Acid (TDA) Production from Marine Sponge Pseudovibrio Species

Characterisation of Non-Autoinducing Tropodithietic Acid (TDA) Production from Marine Sponge Pseudovibrio Species

Tropodithietic acid induces oxidative stress response, cell envelope biogenesis and iron uptake in Vibrio vulnificus

Bacterial Tropone Natural Products and Derivatives: Overview of their Biosynthesis, Bioactivities, Ecological Role and Biotechnological Potential

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