Two of a Kind--The Biosynthetic Pathways of Chlorotonil and Anthracimycin.
Chlorotonil A is a novel polyketide isolated from the myxobacterium Sorangium cellulosum So ce1525 that features a unique gem-dichloro-1,3-dione moiety. It exhibits potent bioactivity, most notably against the problematic malaria pathogen Plasmodium falciparum in the nanomolar range. In addition, strong antibacterial and moderate antifungal activity were determined. The outstanding biological activity of chlorotonil A as well as its unusual chemical structure triggered our interest in elucidating its biosynthesis, a prerequisite for alteration of the scaffold by synthetic biology approaches. This endeavor was facilitated by a recent report describing the strikingly similar structure of anthracimycin from a marine streptomycete, a compound of considerable interest due to its potent antibacterial activity. In this study, we report the identification and characterization of the chlorotonil A biosynthetic gene cluster from So ce1525 and compare it with that for anthracimycin biosynthesis. Access to both gene clusters allowed us to highlight commonalities between the two pathways and revealed striking differences, some of which can plausibly explain the structural differences observed between these intriguing natural products.
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University , Saarbrücken, Germany.
Katrin
K
Jungmann
Helmholtz Centre for Infection Research , Department of Microbial Drugs, Braunschweig, Germany.
Rolf
R
Jansen
Helmholtz Centre for Infection Research , Department of Microbial Drugs, Braunschweig, Germany.
Klaus
K
Gerth
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University , Saarbrücken, Germany.
Volker
V
Huch
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University , Saarbrücken, Germany.
Daniel
D
Krug
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego , La Jolla, California, United States.
William
W
Fenical
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University , Saarbrücken, Germany.
Rolf
R
Müller
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D053898:Biosynthetic Pathways / Q000235:genetics; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000378:metabolism*; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D005810:Multigene Family / Q000235:genetics; D010641:Phenotype; D061065:Polyketides / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D006843:Hydrocarbons, Chlorinated; D018942:Macrolides; D061065:Polyketides; C583934:anthracimycin; C526339:chlorotonil A