Dendrogenin A

A multinational team of researchers in Europe report the discovery of a new antifungal antibiotic named solanimycin. The compound, initially isolated from a pathogenic bacterium that infects potatoes, appears to be produced by a broad spectrum of related plant pathogenic bacteria. The growing threat of antimicrobial resistance has led researchers to search for new compounds everywhere. This week in mBio, a multinational team of researchers in Europe report the discovery of a new antifungal antibiotic named solanimycin. The compound, initially isolated from a pathogenic bacterium that infects potatoes, appears to be produced by a broad spectrum of related plant pathogenic bacteria. Solanimycin acts against a wide range of fungi known to infect and wreak havoc on agricultural crops, according to the researchers. In lab studies, the compound also acted against Candida albicans, a fungus that occurs naturally in the body but can cause dangerous infections. The results suggest that solanimycin, and related compounds, could be useful in both agricultural and clinical settings. Soil microbes, especially from the Actinobacteria phylum, produce most therapeutic antibiotics used today. The new discovery suggests plant-based microorganisms are worth a closer look, especially as crops develop resistance to existing treatments, says microbiologist Rita Monson, Ph.D., at the University of Cambridge. She co-led the study with molecular microbiologist Miguel Matilla, Ph.D., at the Spanish Research Council's Estación Experimental del Zaidín, in Granada. "We have to look more expansively across much more of the microbial populations available to us," Monson said. The pathogenic potato bacterium Dickeya solani, which produces solanimycin, was first identified more than 15 years ago. Researchers in the lab of molecular microbiologist George Salmond, Ph.D., at the University of Cambridge, began investigating its antibiotic potential about a decade ago. "These strains emerged rapidly, and now they are widely distributed," said Matilla. Solanimycin isn't the first antibiotic discovered from the microbe. In previous work, researchers found that D. solani produces an antibiotic called oocydin A, which is highly active against multiple fungal plant pathogens. Those previous discoveries, together with the analysis of the genome of the bacterium, hinted that it might synthesize additional antibiotics, Matilla said, also with antifungal potential. That hint paid off: Matilla, Monson, Salmond and their colleagues found that when they silenced the genes responsible for the production of oocydin A, the bacterium continued to show antifungal activity. That observation led to the identification of solanimycin and the identification of the gene clusters responsible for the proteins that make the compound. The researchers found that the bacterium uses the compound sparingly, producing it in response to cell density. An acidic pH environment -- as that present in a potato -- also activates the solanimycin gene cluster. Monson said it almost looks like a clever protective mechanism. "It's an antifungal that we believe that will work by killing fungal competitors, and the bacteria benefit so much from this," said Monson. "But you don't turn it on unless you're in a potato." Monson said the researchers have begun collaborating with chemists to learn more about the molecular structure of solanimycin and better understand how it works. Then, she and Matilla said they hope to see continued testing of the compound in plant and animal models. "Our future steps are focused on trying to use this antibiotic antifungal for plant protection," Matilla said. The research team see the discovery as an encouraging sign that plant pathogens -- like D. solani -- could be coaxed to make compounds that may be used against diseases in plants and people. "We have to open to the exploration of everything that's out there to find new antibiotics," Matilla said.

CAMBRIDGE, Mass., July 18, 2022 /PRNewswire/ -- Sumitomo Pharma Oncology, Inc., a clinical-stage company focused on novel cancer therapeutics, today announced the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for DSP-0390, an investigational emopamil-binding protein (EBP) inhibitor for the treatment of brain cancer. "This designation for DSP-0390 underscores the profound need for novel brain cancer treatment options," said Patricia S. Andrews, CEO and Global Head of Oncology, Sumitomo Pharma Oncology, Inc. "We are excited to contribute to advancing critical research in brain cancer." The FDA's Orphan Drug Designation is granted to investigational therapies addressing rare medical diseases or conditions that affect fewer than 200,000 people in the United States. Brain cancer refers to brain tumors, made up of abnormal growth of cells in the brain, that are malignant. The exact cause of most brain cancer is unknown.1 "DSP-0390 is an emopamil-binding protein (EBP) inhibitor that mediates de novo cholesterol synthesis for cell membrane structure and signaling, enabling aberrant growth of tumors,"2-5 detailed Jatin J. Shah, M.D., Chief Medical Officer of Sumitomo Pharma Oncology, Inc. "Notably, in patients with glioblastoma multiforme (GBM), a form of high-grade glioma, increased de novo cholesterol synthesis is correlated with poor survival and preclinical evidence has shown that DSP-0390 has cytotoxic activity against GBM cell lines."6 DSP-0390 is currently being evaluated in a Phase 1 clinical trial to evaluate the safety and efficacy of DSP-0390 in patients with recurrent, high-grade glioma, which is being conducted in the United States and Japan. To learn more about the study and eligibility for enrollment, visit clinicaltrials.gov ( NCT05023551). This is the second recently announced Orphan Drug Designations from SMP Oncology. TP-3654, the company's proprietary investigational oral inhibitor of PIM kinases, was also granted Orphan Drug Designation for the treatment of myelofibrosis ( NCT04176198). About DSP-0390 DSP-0390 is an investigational emopamil-binding protein (EBP) inhibitor. EBP is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis.2 DSP-0390 has shown cytotoxic activity against GBM, colorectal cancer, and triple-negative breast cancer in vitro. DSP-0390 is currently being evaluated in a Phase 1, interventional clinical trial to evaluate the safety and efficacy of DSP-0390 in patients with recurrent high-grade glioma ( NCT05023551). About Sumitomo Pharma Oncology, Inc. Sumitomo Pharma Oncology, Inc., is a wholly owned subsidiary of Sumitomo Pharma Co., Ltd. As a global oncology organization with teams in the U.S. and Japan, SMP Oncology is committed to advancing purposeful science by transforming new discoveries into meaningful treatments for patients with cancer. SMP Oncology's robust and diverse pipeline of preclinical and advanced-stage assets spans multiple areas, including oncogenic pathways, survival mechanisms and novel protein interactions, which aim to address unmet clinical needs in oncology. For more information, visit . About Sumitomo Pharma Co., Ltd Sumitomo Pharma Co., Ltd is among the top-ten listed pharmaceutical companies in Japan, operating globally in major pharmaceutical markets, including Japan, the U.S., China, and other Asian countries with about 7,000 employees worldwide. Sumitomo Pharma Co., Ltd defines its corporate mission as "To broadly contribute to society through value creation based on innovative research and development activities for the betterment of healthcare and fuller lives of people worldwide." Additional information about Sumitomo Pharma Co., Ltd is available through its corporate website at . Disclaimer Regarding Forward-Looking Statements This press release contains "forward-looking statements," as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development, and commercialization of pharmaceutical products. The forward-looking statements in this press release are based on management's assumptions and beliefs in light of information presently available and involve both known and unknown risks and uncertainties. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice. References Brain cancer. Updated April 21, 2022. Accessed May 31, 2022. Long T, Hassan A, Thompson BM, McDonald JG, Wang J, LI X. Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition. Nat Commun. 2019;10(1):2452. Yang C, McDonald JG, Patel A, et al. Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem. 2006;281(38):27816-27826. Dong F, Mo Z, Eid W, Courtney KC, Zha X. Akt inhibition promotes ABCA1-mediated cholesterol efflux to apoA-1 through suppressing mTORC1. PLOS ONE. 2014;9(11):e113789. Segala G, David M, de Medina P, et al. Dendrogenin A drives LXR to trigger lethal autophagy in cancers. Nat Commun. 2017;8(1):1903. Kambach DM, Halim AG, Cauer AS, et al. Disabled cell density sensing leads to dysregulated cholesterol synthesis in glioblastoma. Oncotarget. 2017;8(9):14860-14875. SOURCE Sumitomo Pharma Oncology, Inc.