Mechanism of action of oritavancin and related glycopeptide antibiotics

Abstract

Oritavancin (LY333328) is a semisynthetic glycopeptide antibiotic having excellent bactericidal activity against glycopeptide-susceptible and -resistant Gram-positive bacteria. Oritavancin is the N-alkyl-p-chlorophenylbenzyl derivative of chloroeremomycin (LY264826) and is currently in phase III clinical trials for use in Gram-positive infections. Studies show that oritavancin and related alkyl glycopeptides inhibit bacterial cell wall formation by blocking the transglycosylation step in peptidoglycan biosynthesis in a substrate-dependent manner. As with other glycopeptide antibiotics, including vancomycin, the effects of oritavancin on cell wall synthesis are attributable to interactions with dipeptidyl residues of peptidoglycan precursors. Unlike vancomycin, however, oritavancin is strongly dimerized and can anchor to the cytoplasmic membrane, the latter facilitated by its alkyl side chain. Cooperative interactions derived from dimerization and membrane anchoring in situ can be of sufficient strength to enable binding to either dipeptidyl or didepsipeptidyl peptidoglycan residues of vancomycin-susceptible and -resistant enterococci, respectively. This review describes the antibacterial activity of oritavancin, and examines the evidence supporting the proposed mechanism of action for this agent and related analogs.

Peripheral modifications of [Ψ[CH 2 NH]Tpg 4 ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

“…Thus, this inhibition of bacterial cell wall synthesis is not derived from inhibition of transpeptidase-catalyzed cross-linking derived from D-Ala-D-Ala/D-Ala-D-Lac binding but rather, likely arises from direct inhibition of transglycosylase by the peripherally modified disaccharide. Previous studies of Kahne and coworkers (32,33) and others (30,31,55) have shown such direct inhibition of transglycosylase by 5 and related CBP-bearing analogs. Finally, the potent pocket-modified vancomycin analog 8, containing the peripheral CBP modification, inhibits cell wall synthesis more effectively than 4, lacking the CBP modification and more potently than either 5 or 6, lacking a productive pocket modification.…”

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

“…Vancomycin inhibits late-stage peptidoglycan biosynthesis and acts outside the cytoplasmic membrane, which results in the intracellular accumulation of UDP-linked MurNAc-pentapeptide precursors (272,273). The vancomycin complex involves a number of hydrogen bonds between the peptide component of vancomycin and the D-Ala-D-Ala residue (5,15). Any process that interferes with vancomycin binding to D-Ala-D-Ala residues in the cell wall will decrease the potency of the drug.…”

Actinomycetes of Orthosipon stamineus rhizosphere as producer of antibacterial compound against multidrug resistant bacteria

“…The presence of antibiotic and other chemotherapeutic compounds becoming a relief thingeither nowadays or in the future, however it's still not enough yet. The main problem is there is a must for the presence of new medical agents which have a better potency in comparison to what have existed todays [2]. One of effort which can be done is doing a screening of bioactive compound towards any organisms or doing a modification towards the compounds which have existed todays.…”