Discovery and biosynthetic origin of cyclopropanol-substituted toxins in human-pathogenic bacteria Felix Trottmann 1 , Keishi Ishida 1 , Jakob Franke 2 , Ingrid Richter 1 , Michael Cyrulies 3 , Hans-Martin Dahse 4 , Lars Regestein 3 , Aleksa Stanišić 5 , Mie Ishida-Ito 1 , Hajo Kries 5 , Georg Pohnert 6 , Michael Groll 7 , Christian Hertweck 1,8 1 Department of Biomolecular Chemistry, (HKI), Germany, 2 Institute of Botany, Leibniz University Hannover, Germany, 3 Bio Pilot Plant (HKI), Germany, 4 Department Infection Biology (HKI), Germany, 5 Junior Research Group Biosynthetic Design of Natural Products (HKI), Germany, 6 University Jena, Germany, 7 Technical University Munich, Germany, 8 Friedrich Schiller University Jena, Germany The Burkholderia species B. mallei and B.pseudomallei are notorious human pathogens that are also considered potential biowarfare agents. [1] Besides the danger of exposure through deliberate release, 165,000 cases of melioidosis, the disease caused by B. pseudomallei , are estimated to occur annually. [2] Treatment of the often lethal infections is complicated by the pathogens' high resistance to clinically used antibiotics. [1] Despite this eminent threat, the knowledge of effector molecules by which these bacteria induce pathology is limited. [3] This poster will show the discovery and biosynthetic origin of toxic secondary metabolites (malleicyprols) produced by bacteria belonging to the B. pseudomallei complex. Malleicyprols are assembled by an unusual polyketide synthase encoded by the virulence-associated biosynthetic gene cluster bur . [4] A hallmark of the polyketide metabolites is a highly strained cyclopropanol "warhead" that is essential for their detrimental effect. The biosynthetic route to the cyclopropanol warhead starts from ʟ-methionine to produce sulfonium-metabolites known from global sulfur cycling. The key step in cyclopropanol formation is catalysed by a member of the KARI enzyme family, which is widespread among bacterial primary metabolism and plays an important role in branched amino acid biosynthesis. In the case of pathogenic Burkholderia spp. however, this enzyme fold has been repurposed to build the virulence-conferring cyclopropanol structure. The enzymatic mechanism that includes a concealed redox reaction and leads to ring formation will be discussed. References 1. W. J. Wiersinga, H. S. Virk, A. G. Torres, B. J. Currie, S. J. Peacock, D. A. B. Dance, D. Limmathurotsakul, Nat. Rev. Dis. Primers . 2018 , 4, 17107. 2. D. Limmathurotsakul, N. Golding, D. A. B. Dance, J. P. Messina, D. M. Pigott, C. L. Moyes, D. B. Rolim, E. Bertherat, N. P. J. Day, S. J. Peacock, S. I. Hay, Nat. Microbiol. 2016 , 1, 15008. 3. J. B. Biggins, H. S. Kang, M. A. Ternei, D. DeShazer, S. F. Brady, J. Am. Chem. Soc. 2014 , 136, 9484-9490. 4. a) J. B. Biggins, M. A. Ternei, S. F. Brady, J. Am. Chem. Soc. 2012 , 134, 13192-13195; b) J. Franke, K. Ishida, C. Hertweck, Angew. Chem. Int. Ed. 2012 , 51, 11611-11615.
P78
© The Author(s), 2022
Made with FlippingBook Learn more on our blog