New pacidamycin antibiotics through precursor-directed biosynthesis.
Pacidamycins, mureidomycins and napsamycins are structurally related uridyl peptide antibiotics that inhibit translocase I, an as yet clinically unexploited target. This potentially important bioactivity coupled to the biosynthetically intriguing structure of pacidamycin make this natural product a fascinating subject for study. A precursor-directed biosynthesis approach was employed in order to access new pacidamycin derivatives. Strikingly, the biosynthetic machinery exhibited highly relaxed substrate specificity with the majority of the tryptophan analogues that were administered; this resulted in the production of new pacidamycin derivatives. Remarkably, 2-methyl-, 7-methyl-, 7-chloro- and 7-bromotryptophans produced their corresponding pacidamycin analogues in larger amounts than the natural pacidamycin. Low levels or no incorporation was observed for tryptophans substituted at positions 4, 5 and 6. The ability to generate bromo- and chloropacidamycins opens up the possibility of further functionalising these compounds through chemical cross-coupling in order to access a much larger family of derivatives.
Grüschow
Sabine
S
School of Chemical Sciences and Pharmacology, University of East Anglia, Earlham Road, Norwich NR4 7TJ, UK.
Rackham
Emma J
EJ
Elkins
Benjamin
B
Newill
Philip L A
PL
Hill
Lionel M
LM
Goss
Rebecca J M
RJ
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D013058:Mass Spectrometry; D011741:Pyrimidine Nucleosides / Q000096:biosynthesis* / Q000737:chemistry*; D013302:Streptomyces / Q000378:metabolism*; D014364:Tryptophan / Q000737:chemistry
D000900:Anti-Bacterial Agents; D011741:Pyrimidine Nucleosides; D014364:Tryptophan