Oritavancin Diphosphate

Description

Oritavancin diphosphate is a glycopeptide analog related to the vancomycin class of antibiotics that inhibits the transpeptidase and transglycosylation steps of bacterial peptidoglycan cell-wall synthesis. The compound was discovered and initially developed by Eli Lilly and Co. The development of the compound was sold to Intermune and then to Targanta which was acquired by The Medicines Company who achieved approval of the drug by the US FDA for the treatment of acute bacterial skin and skin-structure infections caused by gram-positive bacteria. It is also approved for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections.

The Uses of Oritavancin Diphosphate

Antibacterial (peptidoglycan synthesis inhibitor).

The Uses of Oritavancin Diphosphate

Oritavancin phosphate can be used in biological study of synthesis, properties, and mechanism of action of new generation of polycyclic glycopeptide antibiotics.

Definition

ChEBI: A phosphate salt obtained by combining oritavancin with two molar equivalents of phosphoric acid. Used for the treatment of acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible isolates of designated Gram-posit ve microorganisms.

Biochem/physiol Actions

Oritavancin is a lipoglycopeptide vancomycin analog with broad spectrum activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and organisms resistant to vancomycin and other antibiotics such as linezolid and daptomycin. Oritavancin has multiple mechanisms of action, including inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin also has a long half-life, allowing for a single intravenous dose of rather than the standard vacomycin treatment of twice-daily infusions for ten days.

Synthesis

Commercial eremomycin (217) was treated with 40-chlorobiphenylcarboxaldehyde (218) followed by sodium cyanoborohydride in refluxing methanol to give oritavancin. Interestingly, there are three amino groups within eremomycin that can undergo reductive alkylation, and this chemistry preferentially occurs at the disaccharide amino group. The reaction is reported to occur in 69% crude yield and giving 16¨C18% yield of oritavancin after high performance liquid chromatography (HPLC) purification. No experimental details were found describing the preparation of the diphosphate salt, but presumably this occurs through treatment with phosphoric acid and crystallization to give oritavancin diphosphate (XXVI).