Biosynthesis of ketomycin. (II) biomimetic model for beta-lactamase catalysis: host-guest interactions in cyclodextrin-penicillin inclusion complex

Thesis/Dissertation · Wed Jan 01 04:00:00 EST 1986

OSTI ID:7002130

Mak, H W

The antibiotic ketomycin is formed from shikimic acid via chorismic acid and prephenic acid. Phenylalanine and 2',5'-dihydrophenylalanine derived from shikimic acid are not intermediates in the biosynthesis. Degradation of ketomycin derived from (1,6-/sup 14/C)shikimic acid showed that prephenic acid is converted into ketomycin with stereospecific discrimination between the two enantiotopic edges of the ring, the pro-S-R edge giving rise to the C-2', C-3' side of the cyclohexane ring of ketomycin. The resistance of pathogenic bacteria to the action of ..beta..-lactam antibiotics is mainly ascribed to their ability to produce ..beta..-lactamase to cleave the ..beta..-lactam ring. It is essential to understand the molecular nature of ..beta..-lactamase-penicillin recognition for designing and formulating more effective ..beta..-lactam antibiotics. A biomimetic study of ..beta..-lactamase is therefore initiated. To meet the requirements of hydrophobic and serine protease characteristics of ..beta..-lactamase, ..cap alpha..-cyclodextrin is chosen as a biomimetic model for ..beta..-lactamase. The structural specificity and the chemical dynamics of ..cap alpha..-cyclodextrin-phenoxymethyl penicillin inclusion complex in solid state and in solution have been determined by IR and NMR spectroscopy. The spectral results strongly indicate that the phenyl portion of the phenoxymethyl penicillin forms a stable inclusion complex with the hydrophobic cavity of ..cap alpha..-cyclodextrin in solution as well as in the solid state. Kinetic studies followed by /sup 1/HNMR and HPLC analyses under alkaline condition have shown that the ..cap alpha..-cyclodextrin mimics the catalytic function of serine of ..beta..-lactamase in the stereospecific hydrolysis of the ..beta..-lactam ring of phenoxymethyl penicillin.

• Research Organization: Purdue Univ., Lafayette, IN (USA)
• OSTI ID: 7002130
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMIDES
AMINO ACIDS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
BACTERIA
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MODELS
BIOSYNTHESIS
CARBON 14 COMPOUNDS
CARBOXYLIC ACIDS
CATALYSIS
CHEMICAL REACTIONS
CHROMATOGRAPHY
CYCLASES
DECOMPOSITION
DRUGS
ENZYMATIC HYDROLYSIS
ENZYME ACTIVITY
ENZYMES
HYDROLYSIS
HYDROXY ACIDS
INFRARED SPECTRA
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LACTAMS
LIGANDS
LIQUID COLUMN CHROMATOGRAPHY
LYASES
LYSIS
MICROORGANISMS
NMR SPECTRA
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PENICILLIN
REACTION KINETICS
SEPARATION PROCESSES
SERINE
SHIKIMIC ACID
SOLVOLYSIS
SPECTRA
STRUCTURAL CHEMICAL ANALYSIS
SYNTHESIS
TRACER TECHNIQUES