A genomic screening approach to the structure-guided identification of drug candidates from natural sources.
The potential of actinomycetes to produce natural products has been exploited for decades. Recent genomic sequence analyses have revealed a previously unrecognized biosynthetic potential and diversity. In order to rationally exploit this potential, we have developed a sequence-guided genetic screening strategy. In this "genome mining" approach, genes that encode tailoring enzymes from natural product biosyntheses pathways serve as indicator genes for the identification of strains that have the genetic potential to produce natural products of interest. We chose halogenases, which are known to be involved in the synthesis of halometabolites as representative examples. From PCR screening of 550 randomly selected actinomycetes strains, we identified 103 novel putative halogenase genes. A phylogenetic analysis of the corresponding putative halogenases, and the determination of their sequential context with mass spectrometric analysis of cultures filtrates revealed a distinct correlation between the sequence and secondary metabolite class of the halometabolite. The described screening strategy allows rapid access to novel natural products with predetermined structural properties.
Hornung
Andreas
A
Combinature Biopharm AG, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
Bertazzo
Marcelo
M
Dziarnowski
Agnieszka
A
Schneider
Kathrin
K
Welzel
Katrin
K
Wohlert
Sven-Eric
SE
Holzenkämpfer
Meike
M
Nicholson
Graeme J
GJ
Bechthold
Andreas
A
Süssmuth
Roderich D
RD
Vente
Andreas
A
Pelzer
Stefan
S
D000595:Amino Acid Sequence; D001483:Base Sequence; D001688:Biological Products; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D023281:Genomics; D009682:Magnetic Resonance Spectroscopy; D008403:Mass Screening; D008969:Molecular Sequence Data; D015394:Molecular Structure; D004364:Pharmaceutical Preparations; D017386:Sequence Homology, Amino Acid
D001688:Biological Products; D017931:DNA Primers; D004364:Pharmaceutical Preparations