Category Archives: Former Lab Members

Antimicrobial nucleoside antibiotics targeting cell wall assembly: Recent advances in structure-function studies and nucleoside biosynthesis

Michael Winn ; Rebecca J. M. Goss ; Ken-ichi Kimura ; Timothy D. H. Bugg

Nat Prod Rep 2010, 27 279-304

The quest for new antibiotics, especially those with activity against Gram-negative bacteria, is urgent; however, very few new antibiotics have been marketed in the last 40 years, with this limited number falling into only four new structural classes. Several nucleoside natural product antibiotics target bacterial translocase MraY, involved in the lipid-linked cycle of peptidoglycan biosynthesis, and fungal chitin synthase. Biosynthetic studies on the nikkomycin, caprazamycin and pacidamycin/
mureidomycin families are also reviewed.

New pacidamycins biosynthetically: probing N- and C-terminal substrate specificity

Amany E. Ragab ; Sabine Grüschow ; Emma J. Rackham ; Rebecca J. M. Goss

Org Biomol Chem 2010, 8 3128-3129

Feeding phenylalanine analogues to Streptomyces coeruleorubidus reveals the remarkable steric and electronic flexibility of this biosynthetic pathway and leads to the generation of a series of new halopacidamycins.

Graphical abstract: New pacidamycins biosynthetically: probing N- and C-terminal substrate specificity

New Pacidamycin Antibiotics Through Precursor-Directed Biosynthesis

Sabine Gruschow ; Emma J. Rackham ; Benjamin Elkins ; Philip L. A. Newilll ; Lionel M. Hill ; Rebecca J. M. Goss

ChemBioChem 2009, 10 (2) 355-360

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.

A convenient one-step synthesis of L-aminotryptophans and improved synthesis of 5-fluorotryptophan

Michael Winn ; Abhijeet Deb Roy ; Sabine Grüschow ; Raj S. Parameswaran ; Rebecca J. M. Goss

Bioorg Med Chem Lett 2008, 18 (16) 4508-4510

A one-pot biotransformation for the generation of a series of l-aminotryptophans using a readily prepared protein extract containing tryptophan synthase is reported. The extract exhibits remarkable stability upon freeze-drying, and may be stored and used for long periods after its preparation without significant loss of activity.

Generating rapamycin analogues by directed biosynthesis: starter acid substrate specificity of mono-substituted cyclohexane carboxylic acids

Rebecca J. M. Goss ; Simon E. Lanceron ; Nicola J. Wise ; Steven J. Moss

Org Biomol Chem 2006, 4, 4071-4073

We report a convenient synthesis of 4-fluorocyclohexanoic acid, and an insight into the rules governing acceptance of starter acid analogues in the precursor-directed biosynthesis of rapamycin.

Graphical abstract: Generating rapamycin analogues by directed biosynthesis: starter acid substrate specificity of mono-substituted cyclohexane carboxylic acids