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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM090327-05
Application #
8583328
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Anderson, Vernon
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$263,638
Indirect Cost
$85,438
Name
Georgia Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
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