That Beta-lactam antibiotics account for approximately 10% of world-wide ethical drugs sales attests to their importance in combatting bacterial infections in man. In this renewal application a research program is detailed to continue biosynthetic studies of (1) the monocyclic Beta-lactams represented by the nocardicins and the monobactams, (2) the important lactamase inhibitor, clavulanic acid, and the related, antipodal clavams, and (3) the carbapenems using carbapenem-3-carboxylate, the simplest structurally of this family, as the experimental system. Groundwork successfully laid in the current grant period in cell- free studies and enzymology will be expanded and applied with ongoing synthetic, spectroscopic and stereochemical approaches to understanding the fundamental biosynthetic steps responsible for Beta-lactam antibiotic formation. The knowledge to be gained in studies of this kind will lead to improved production of these valuable commodities through incorporation of multiple copies of key biosynthetic genes in commercial fermentation strains, and could in the future provide modified structural types with improved pharmacological properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI014937-11
Application #
3125938
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1978-09-01
Project End
1994-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
11
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Arts and Sciences
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Long, Darcie H; Townsend, Craig A (2018) Mechanism of Integrated ?-Lactam Formation by a Nonribosomal Peptide Synthetase during Antibiotic Synthesis. Biochemistry 57:3353-3358
Oliver, Ryan A; Li, Rongfeng; Townsend, Craig A (2018) Monobactam formation in sulfazecin by a nonribosomal peptide synthetase thioesterase. Nat Chem Biol 14:5-7
Li, Rongfeng; Oliver, Ryan A; Townsend, Craig A (2017) Identification and Characterization of the Sulfazecin Monobactam Biosynthetic Gene Cluster. Cell Chem Biol 24:24-34
Harari, Colin M; Magagna, Michelle; Bedoya, Mariajose et al. (2016) Microwave Ablation: Comparison of Simultaneous and Sequential Activation of Multiple Antennas in Liver Model Systems. Radiology 278:95-103
Townsend, Craig A (2016) Convergent biosynthetic pathways to ?-lactam antibiotics. Curr Opin Chem Biol 35:97-108
Marous, Daniel R; Lloyd, Evan P; Buller, Andrew R et al. (2015) Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis. Proc Natl Acad Sci U S A 112:10354-8
Gaudelli, Nicole M; Long, Darcie H; Townsend, Craig A (2015) ?-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis. Nature 520:383-7
Gaudelli, Nicole M; Townsend, Craig A (2014) Epimerization and substrate gating by a TE domain in ?-lactam antibiotic biosynthesis. Nat Chem Biol 10:251-8
Buller, Andrew R; Freeman, Michael F; Schildbach, Joel F et al. (2014) Exploring the role of conformational heterogeneity in cis-autoproteolytic activation of ThnT. Biochemistry 53:4273-81
Li, Rongfeng; Lloyd, Evan P; Moshos, Kristos A et al. (2014) Identification and characterization of the carbapenem MM 4550 and its gene cluster in Streptomyces argenteolus ATCC 11009. Chembiochem 15:320-31

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