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Abstract

Abstract: LONG TERM GOAL: Production of novel ketolide antibiotics with potent antibacterial activity against macrolide susceptible and resistant bacterial pathogens. PHASE I: We will develop a biological process for production of 15-methyl-6- deoxyerythronolide B, the precursor of 15-methylerythromycin A, through genetic engineering of the 6-deoxyerythronolide B polyketide synthase. This will be accomplished by optimizing the biosynthetic pathway of a substrate used to make the target compound in Streptomyces coelicor, a related actinomycete strain of Escherichia coli. That substrate will be used by an engineered 6-deoxyerythronolide B polyketide synthase to make 15-methyl-6-deoxyerythronolide B, which will be isolated and bioconverted to 15-methylerythromycins by a strain of Saccharopolyspora erythraea or directly to this compound by an engineered strain of Streptomyces fradiae that contains the genes for production of 15-methyl-deoxyerythronolide B and the 15- methylerythromycins. PHASE II: This process will be optimized for large scale production of 15- methyerythromycins that will be used to make ketolide antibiotics in sufficient amount for preclinical and clinical development. Kosan has discovered a lead ketolide in partnership with The R.W. Johnson Pharmaceutical Research Institute and expects that this compound or a close analog will be developed into a drug that is competitive with the two current front runners in this area. PROPOSED COMMERCIAL APPLICATIONS: There is a growing need to discover and develop noel antibiotics that can overcome resistance mechanisms. The proposed research will generate modified macrolide antibiotics which are effective against macrolide resistant organisms. Since world-wide sales of macrolide antibiotics exceed $3B per year, these new antibiotics should have significant commercial value.

Thesaurus Terms:
Escherichia coli, Streptomyces, antibacterial agent, drug design /synthesis /production, drug discovery /isolation, erythromycin, macrolide antibiotic
bacteria infection mechanism, bacteriolysis, biotherapeutic agent, biotransformation, cholinesterase, coenzyme A, combinatorial chemistry, drug resistance, enzyme activity, enzyme biosynthesis, microorganism disease chemotherapy, microorganism immunology, molecular genetics, polyketide synthase
biotechnology, polymerase chain reaction

Institution:	KOSAN BIOSCIENCES
	3832 BAY CENTER PL
	HAYWARD, CA 94545
Fiscal Year:	2002
Department:
Project Start:	15-FEB-2002
Project End:	31-MAY-2003
ICD:	NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG:	ZRG1