Daptomycin

The accelerated appearance of antibiotic resistance presents a serious and growing global health risk. Despite the increasing need for new antibacterial agents, only two mechanistically and structurally new antibiotics have reached the clinic in the past 40 years: linezolid and daptomycin. While linezolid is of synthetic origin, daptomycin (Fig. 1) is a natural product isolated from fermentations of Streptomyces roseosporus. Daptomycin is rapidly bactericidal against Staphylococcusaureus, including methicillin-resistant S. aureus (MRSA), vanco-mycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) strains. Marketed under the trade name Cubicin, daptomycin is the first lipopeptide antibiotic of its kind to be approved for clinical use. Structurally unique, daptomycin is a cyclic depsipeptide composed of 13 amino acids (including non-proteinogenic and D-amino acids) and bears an N-terminal 10-carbon lipophilic tail.

Although these are the current drugs used for biofilm related infections, there are serious concerns. Daptomycin, which acts on the bacterial membrane in a calcium dependent manner, has been shown to have reduced susceptibility to a variety ofMRSA strains and is also proved ineffective in biofilm-related and deep seated infections. Likewise, bacterial developmentofresistancetovancomycinisnotableduetothe emergence of vancomycin intermediate S. aureus (VISA) and vancomycin-resistant Enterococci (VRE) strains. Moreover, a combined pharmacodynamic qualitative and quantitative S. aureus biofilm model shows the failure of vancomycin against mature MRSA biofilms. In addition, vancomycin was also ineffective after one day against biofilm formed by catheter associated MRSA. Several therapeutic procedures have been recorded failure for daptomycin/vancomycin therapy in MRSA and susceptible S. aureus clinical isolates that are not susceptible to daptomycin. In addition, the newest antibiotics talavancin shows renal failure and teratogenic effects. All these facts imply that we are running short of potent antimicrobials. Thus, it is urgent to search for new options.

In addition to the critical role of charges for cell bacterial physiology, it is obvious that negatively-charged lipids are critical for the action of membrane-active antibiotics including e.g. daptomycin, dalbavancin, polymyxins. First, negatively-charged lipids like PG and CL are critical for the ability of daptomycin to oligomerize inside of the bacterial cell membrane and to form oligomeric transmembrane pores induced by the daptomycin–calcium complexes. Second, ionic character as observed after derivatization or conversion of the carboxy group into an ester, amide or hydrazide highly modulates the relative activity of teicoplanin-type glycopeptides like dalbavancin, especially against coagulase negative Staphylococcus.

Daptomycin (CubicinR ) is a cyclic lipopeptide antibiotic approved in the USA in 2003 for the treatment of skin and skin structure infections caused by Gram-positive pathogens. Daptomycin is produced by fermentation of Streptomyces roseosporus. S. roseosporus normally produces a complex of lipopeptides (A21978C) with different long-chain fatty acid tails; daptomycin, a member of the A21978C complex that contains a straight C10 lipid side-chain, is produced in quantity by feeding decanoic acid during fermentation. The peptide portion of daptomycin contains 13 amino acids, including three with D-stereochemistry. The cyclic portion contains 10 residues linked by an ester bond between the terminal kynurenine (Kyn) and the hydroxyl group of Thr.