Isolation and identification of rhizoxin analogs from Pseudomonas fluorescens Pf-5 by using a genomic mining strategy.
The products synthesized from a hybrid polyketide synthase/nonribosomal peptide synthetase gene cluster in the genome of Pseudomonas fluorescens Pf-5 were identified using a genomics-guided strategy involving insertional mutagenesis and subsequent metabolite profiling. Five analogs of rhizoxin, a 16-member macrolide with antifungal, phytotoxic, and antitumor activities, were produced by Pf-5, but not by a mutant with an insertion in the gene cluster. The five rhizoxin analogs, one of which had not been described previously, were differentially toxic to two agriculturally important plant pathogens, Botrytis cinerea and Phytophthora ramorum. The rhizoxin analogs also caused swelling of rice roots, a symptom characteristic of rhizoxin itself, but were less toxic to pea and cucumber roots. Of the rhizoxin analogs produced by Pf-5, the predominant compound, WF-1360 F, and the newly described compound 22Z-WF-1360 F were most toxic against the two plant pathogens and three plant species. These rhizoxin analogs were tested against a panel of human cancer lines, and they exhibited potent but nonselective cytotoxicity. This study highlights the value of the genomic sequence of the soil bacterium P. fluorescens Pf-5 in providing leads for the discovery of novel metabolites with significant biological properties.
Loper
Joyce E
JE
Horticultural Crops Research Laboratory, Agricultural Research Service, United States Department of Agriculture, Corvallis, Oregon 97330, USA.
Henkels
Marcella D
MD
Shaffer
Brenda T
BT
Valeriote
Frederick A
FA
Gross
Harald
H
D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D020171:Botrytis / Q000187:drug effects; D045744:Cell Line, Tumor; D028462:Cucumis / Q000187:drug effects; D023281:Genomics; D006801:Humans; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D005810:Multigene Family; D016254:Mutagenesis, Insertional; D012275:Oryza / Q000187:drug effects; D018532:Pisum sativum / Q000187:drug effects; D010453:Peptide Synthases / Q000235:genetics; D010838:Phytophthora / Q000187:drug effects; D018517:Plant Roots / Q000187:drug effects; D048630:Polyketide Synthases / Q000235:genetics; D011551:Pseudomonas fluorescens / Q000737:chemistry* / Q000201:enzymology / Q000235:genetics*
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D018942:Macrolides; D048630:Polyketide Synthases; C041443:rhizoxin; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase