Synthetic Approaches to Tetracyclines and Mechanisms of Resistance
Wednesday, November 30, 2005
Organizers: Tarek Mansour and Magid Abou-Gharbia, Wyeth Research
Recent years have seen an increasing level of dialogue between chemists and biologists, the lines of communication consolidated by the availability of recombinant biotechnology tools for manipulating the chemical structure of genes, and the proteins they encode. This has led to an explosion of interdisciplinary activity at the chemistry/biology interface, now coined chemical biology. Meetings of this group provide a forum for lively discussion and for establishing connections, and perhaps collaborations, between chemists armed with novel technologies and biologists receptive to using these approaches to solve their chosen biological problem.
Program
Yi Tang, UCLA
"Tetracycline Biosynthesis: Gene Cluster Information and Early Reconstitution Studies."
Phaik-Eng Sum, Wyeth Research
"The Discovery of Tygacil : Representative of a New Class of Antibacterial Agents - Glycylcyclines."
Patricia Bradford, Wyeth Research
"Tygacil, a Novel Glycylcycline Antibiotic: Mechanisms of Action, Antibacterial Activity and Mechanisms of Resistance."
Abstracts
"Tetracycline Biosynthesis: Gene Cluster Information and Early Reconstitution Studies"
Yi Tang
Tetratracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases (PKSs). Understanding the biochemistry of tetracycline PKSs is important towards the rational and combinatorial manipulation of tetracycline biosynthesis. Towards this end, we have sequenced the entire gene cluster of oxytetracycline (oxy, otc) PKS from Streptomyces rimosus. Sequence analysis revealed a total of twenty-one genes within the otrA and otrB resistance genes. In vivo reconstitution using Streptomyces coelicolor revealed that the minimal PKS and a novel amidotransferase, OxyD, are necessary and sufficient for the biosynthesis of amidated polyketides. A novel alkaloid (WJ35) was synthesized as the major product when the oxy minimal PKS, the C9 ketoreductase (OxyJ) and OxyD were coexpressed in S. coelicolor. WJ35 is an isoquinolone compound derived from an amidated decaketide backbone and cyclized with novel regioselectivity. Coexpression of additional oxy biosynthetic enzymes further tailored the amidated tetracycline backbone into novel chemical scaffolds.
"The Discovery of Tygacil : Representative of a New Class of Antibacterial Agents - Glycylcyclines"
Phaik-Eng Sum
Tetracyclines have been used therapeutically as broad-spectrum antibiotics since 1948. The emergence of drug-resistant bacteria has posed a growing challenge to public health and underscored the need for new antibiotics for the treatment of drug resistant infections. A semi-synthetic program was initiated to identify new derivatives with activity against tetracycline-resistant strains. We reasoned that peptidic attachment at ring D, especially at the 9-position might enhance permeation while maintaining ribosome binding. The strategy of using 9-amino-mino as starting point for the synthesis provided accessibility to a number of new derivatives for structure-activity relationship study. This led to the design and synthesis of a series of novel compounds that have been referred to as glycylcycline. One of the glycylcyclines, Tygacil (also known as tigecycline, GAR-936 or TBG-MINO) was selected for further development. It has an expanded broad-spectrum of antibacterial activity both in vitro and in vivo. It is active against bacterial strains carrying either or both of the two major forms of tetracycline resistance (efflux and ribosomal protection). Most importantly, it is active against the multiply antibiotic resistant gram-positive pathogenic bacteria, especially methicillin resistant Staphylococcus aureus (MRSA) (MIC 0.5 microg/ml), vancomycin resistant enterococci