Method for late introduction of the (8r) hydroxyl group carbapenem beta-lactam antibiotic synthesis
AssigneeThe Johns Hopkins University
InventorsCRAIG ARTHUR TOWNSEND, MICAH JEFFREY BODNER, RYAN MARTIN PHELAN, MICHAEL FRANCIS FREEMAN
Life of this patent
Estimating the term…
Abstract
The presently disclosed subject matter demonstrates that ThnG and ThnQ enzymes encoded by the thienamycin gene cluster in Streptomyces cattleya oxidize the C-2 and C-6 moieties of carbapenems, respectively. ThnQ stereospecifically hydroxylates PS-5 giving N-acetyl thienamycin. ThnG catalyzes sequential desaturation and sulfoxidation of PS-5, giving PS-7 and its sulfoxide. The ThnG and ThnQ enzymes are relatively substrate selective, but give rise to the oxidative diversity of carbapenems produced by S. cattleya, and orthologues likely function similarly in allied streptomyces.
Claims9
1-4. (canceled)
A process for preparing a carbapenem of Formula (II):
- the process comprising contacting or incubating a carbapenem substrate of Formula (IIa):
- with a ThnG enzyme under reaction conditions to produce the carbapenem of Formula (II);
- wherein:
- R1 is H;
- R2 is selected from the group consisting of, —NH-glycyl, —NH-beta-alanyl, —NHC(═O)CH2CH2CH2NH2, —NH-pantethienic acid amide, an acyl group comprising C1-C10 substituted and unsubstituted linear and branched alkyl, which can further comprise one or more 3-6 member cycloalkyl rings;
- and
- R3 is H.
A process for preparing a carbapenem of Formula (III):
- the process comprising contacting or incubating a carbapenem substrate of Formula (IIIa):
- with a ThnG enzyme under reaction conditions to produce a carbapenem of Formula (IIIb):
- then contacting or incubating the carbapenem of Formula (IIIb) with a ThnG enzyme under reaction conditions to produce a carbapenem of Formula (III);
- wherein:
- R1 is H;
- R2 is selected from the group consisting of —NH-glycyl, —NH-beta-alanyl, —NHC(═O)CH2CH2CH2NH2, —NH-pantethenic acid amide, an acyl group comprising C1-C10 substituted and unsubstituted linear and branched alkyl, which can further comprise one or more 3-6 member cycloalkyl rings;
- and
- R3 is H.
Dependencies are inferred from the claim text.