ArticleProceedings of the National Academy of Sciences of the United States of America2016
Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 83 citations in OpenAlex.
- Siwa spring microbiomes as reservoirs of biosynthetic gene clusters: Unlocking natural product potential.World journal of microbiology & biotechnology · 2026Article
- Re-examining the iron paradox: the influence of growth medium on regulation and functionality of the tropodithietic acid (TDA) biosynthetic pathway in Phaeobacter piscinae.FEMS microbiology ecology · 2026Article
- Charting a Sustainable Course:Microorganisms · 2026Article
- Identification and Biosynthesis of Tropodithietic Acid byInternational journal of molecular sciences · 2026Article
- Microbial Interactions in Rearing Systems for Marine Fish Larvae.Microorganisms · 2025Review
- Autecology of an oscillating population of a novel host-associatedISME communications · 2025Article
- Genomic Features and Antimicrobial Activity ofMarine drugs · 2024Article
- Unraveling the genomic secrets of Tritonibacter mobilis AK171: a plant growth-promoting bacterium isolated from Avicennia marina.BMC genomics · 2024Article
- Antagonistic activity ofApplied and environmental microbiology · 2024Article
- Industrial and Pharmaceutical Applications of Microbial Diversity of Hypersaline Ecology from Lonar Soda Crater.Current pharmaceutical biotechnology · 2024Review
- Biosynthesis enhancement of tropodithietic acid (TDA) antibacterial compound through biofilm formation by marine bacteriaRSC advances · 2023Article
- The potential to produce tropodithietic acid by Phaeobacter inhibens affects the assembly of microbial biofilm communities in natural seawater.NPJ biofilms and microbiomes · 2023Article
- Article
- The ability of Phaeobacter inhibens to produce tropodithietic acid influences the community dynamics of a microalgal microbiome.ISME communications · 2022Article
- The Small-Molecule Language of Dynamic Microbial Interactions.Annual review of microbiology · 2022Review
- Trade-offs of lipid remodeling in a marine predator-prey interaction in response to phosphorus limitation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Bacterial Community Assembly, Succession, and Metabolic Function during Outdoor Cultivation ofmSphere · 2022Article
- Role is in the eye of the beholder-the multiple functions of the antibacterial compound tropodithietic acid produced by marine Rhodobacteraceae.FEMS microbiology reviews · 2022Article
- Algal p-coumaric acid induces oxidative stress and siderophore biosynthesis in the bacterial symbiont Phaeobacter inhibens.Cell chemical biology · 2022Article
- Article
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4 authors at 1 institution in 1 country.
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Abstract
While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal-bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA's cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed.
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