The thiopeptides, also referred to as pyridinyl polythiazolyl peptides, are a large family of peptide antibiotics that have undergone extensive posttranslational modification. Thiostrepton, like the other thiopeptides, has potent activity against Gram-positive bacteria, including those resistant to current antimicrobial treatments. The thiopeptides have also been reported to possess antimalarial and even anticancer properties. The process by which a fairly simple precursor peptide is converted to the highly complex molecular framework that characterizes this family of antibiotics is poorly understood. There are two main aspects to thiostrepton biosynthesis. The first is the tailoring of the peptide backbone that includes the dehydration of multiple serine and threonine side chains, the introduction of several thiazole rings, side chain oxidations, addition of an unusual quinaldic acid substituent, and the generation of two macrocyclic rings. The mechanism to introduce the dehydropiperidine ring of one of thiostrepton's macrocycles is the subject of much speculation. A separate aspect of thiostrepton biosynthesis is the generation of the quinaldic acid substituent from tryptophan. Our goals are: (1) To delineate the sequential steps required to produce this highly complex metabolite, (2) to characterize the unique enzymatic transformations of this pathway, and (3) investigate the utility of the thiostrepton biosynthetic machinery to generate new thiopeptides that can be evaluated for their antibacterial, antimalarial, and anticancer properties.
Resistance of bacteria to existing antimicrobial agents is a growing concern. The thiopeptide antibiotics are characterized by their extremely potent antibacterial properties, but are also reported to demonstrate antimalarial and anticancer activities. We are proposing to study how these compounds are naturally constructed and apply the knowledge gained toward the production the first therapeutic agents based upon the thiopeptide framework.
| Ichikawa, Hiro; Bashiri, Ghader; Kelly, Wendy L (2018) Biosynthesis of the Thiopeptins and Identification of an F420H2-Dependent Dehydropiperidine Reductase. J Am Chem Soc 140:10749-10756 |
| Zhang, Feifei; Li, Chaoxuan; Kelly, Wendy L (2016) Thiostrepton Variants Containing a Contracted Quinaldic Acid Macrocycle Result from Mutagenesis of the Second Residue. ACS Chem Biol 11:415-24 |
| Blaszczyk, Anthony J; Silakov, Alexey; Zhang, Bo et al. (2016) Spectroscopic and Electrochemical Characterization of the Iron-Sulfur and Cobalamin Cofactors of TsrM, an Unusual Radical S-Adenosylmethionine Methylase. J Am Chem Soc 138:3416-26 |
| Zhang, Feifei; Kelly, Wendy L (2015) Saturation mutagenesis of TsrA Ala4 unveils a highly mutable residue of thiostrepton A. ACS Chem Biol 10:998-1009 |
| Li, Chaoxuan; Zhang, Feifei; Kelly, Wendy L (2012) Mutagenesis of the thiostrepton precursor peptide at Thr7 impacts both biosynthesis and function. Chem Commun (Camb) 48:558-60 |
