New Lipoglycopeptides

Abstract

Dalbavancin, oritavancin and telavancin are semisynthetic lipoglycopeptides that demonstrate promise for the treatment of patients with infections caused by multi-drug-resistant Gram-positive pathogens. Each of these agents contains a heptapeptide core, common to all glycopeptides, which enables them to inhibit transglycosylation and transpeptidation (cell wall synthesis). Modifications to the heptapeptide core result in different in vitro activities for the three semisynthetic lipoglycopeptides. All three lipoglycopeptides contain lipophilic side chains, which prolong their half-life, help to anchor the agents to the cell membrane and increase their activity against Gram-positive cocci. In addition to inhibiting cell wall synthesis, telavancin and oritavancin are also able to disrupt bacterial membrane integrity and increase membrane permeability; oritavancin also inhibits RNA synthesis. Enterococci exhibiting the VanA phenotype (resistance to both vancomycin and teicoplanin) are resistant to both dalbavancin and telavancin, while oritavancin retains activity. Dalbavancin, oritavancin and telavancin exhibit activity against VanB vancomycin-resistant enterococci. All three lipoglycopeptides demonstrate potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis regardless of their susceptibility to meticillin, as well as Streptococcus spp. Both dalbavancin and telavancin are active against vancomycin-intermediate S. aureus (VISA), but display poor activity versus vancomycin-resistant S. aureus (VRSA). Oritavancin is active against both VISA and VRSA. Telavancin displays greater activity against Clostridium spp. than dalbavancin, oritavancin or vancomycin. The half-life of dalbavancin ranges from 147 to 258 hours, which allows for once-weekly dosing, the half-life of oritavancin of 393 hours may allow for one dose per treatment course, while telavancin requires daily administration. Dalbavancin and telavancin exhibit concentration-dependent activity and AUC/MIC (area under the concentration-time curve to minimum inhibitory concentration ratio) is the pharmacodynamic parameter that best describes their activities. Oritavancin's activity is also considered concentration-dependent in vitro, while in vivo its activity has been described by both concentration and time-dependent models; however, AUC/MIC is the pharmacodynamic parameter that best describes its activity. Clinical trials involving patients with complicated skin and skin structure infections (cSSSIs) have demonstrated that all three agents are as efficacious as comparators. The most common adverse effects reported with dalbavancin use included nausea, diarrhoea and constipation, while injection site reactions, fever and diarrhoea were commonly observed with oritavancin therapy. Patients administered telavancin frequently reported nausea, taste disturbance and insomnia. To date, no drug-drug interactions have been identified for dalbavancin, oritavancin or telavancin. All three of these agents are promising alternatives for the trea...

Antimicrobial Peptides: New Frontiers in the Therapy of Infections

“…This example confirms the growing opinion that peptide-based antibiotics will be among the next generation of antiinfective therapy (Mangoni & Shai, 2011). Dalbavancin, oritavancin and telavancin are semisynthetic lipoglycopeptides active against multidrug-resistant Gram-positive pathogens (Zhanel et al, 2010). These molecules share a heptapeptide core that affects cell wall synthesis by inhibiting transglycosilation and transpeptidation, and contain lipophilic side chains that facilitate binding to cell membranes and increase antibacterial activity.…”

Comparative In Vitro Activities of Oritavancin, Dalbavancin, and Vancomycin against Methicillin-Resistant Staphylococcus aureus Isolates in a Nondividing State

“…Oritavancin has multiple mechanisms of action, and its rapid concentration-dependent bactericidal activity against S. aureus isolates in vitro results from a combination of cell wall synthesis inhibition and perturbation of membrane barrier function (4,5). The timedependent bactericidal activity of dalbavancin results from inhibition of cell wall synthesis via a mechanism of action that is shared with the prototypic glycopeptide vancomycin (6)(7)(8). The differences in the mechanisms of action among these agents may be important determinants of their activities against bacteria in a nondividing state.…”

Enhancement of antibiotic-activity through complexation with metal ions - Combined ITC, NMR, enzymatic and biological studies

“…[18][19][20][21][22][23][24] Since conventional approaches to develop MBL inhibitors have been unsuccessful so far, alternative methods are needed. One possible tactic to increase the activity of antibiotics involves their complexation with metal cations.…”