Daptomycin membranes

Daptomycin causes membrane depolarization in bacteria and prevents membrane transport. 

Daptomycin has a unique mechanism of action it disrupts the bacterial membrane of Gram-positive organisms by forming channels across it. These channels permit the leakage of intracellular ions, eventually leading to cell death. Resistance to daptomycin is rare, at least so far. 

Daptomycin (15 Cubicin ) Daptomycin (15) Lipopeptide NP Microbial Antibacterial Disrupts multiple aspects of bacterial cell membrane function 211-225... 

Daptomycin 1980 Lipo peptide Bacterial Cell Membrane... 

Compounds that disrupt cell membrane integrity either through structural or functional disorganization lead to loss of viability. Polymyxins and daptomycin (Fig. 5) are examples of cell membrane inhibitors. 

A novel cyclic lipopeptide antibiotic was isolated from cultures of Strep-tomyces roseosporus grown in the presence of decanioc acid. Daptomycin interacts with the bacterial cell membrane and interferes with membrane potential.Unlike polymyxin B, daptomycin can target majority of clinically relevant Gram-positive pathogens. 

OTHER CELL WALL- OR MEMBRANE-ACTIVE AGENTS DAPTOMYCIN... 

Proposed mechanism of action of daptomycin. Daptomycin first binds to the cytoplasmic membrane (step 1) and then forms complexes in a calcium-dependent manner (steps 2 and 3). Complex formation causes a rapid loss of cellular potassium, possibly by pore formation, and membrane depolarization. This is followed by arrest of DNA, RNA, and protein synthesis resulting in cell death. Cell lysis does not occur. 

Daptomycin Binds to cell membrane, causing depolarization and rapid cell death Bactericidal activity against susceptible bacteria more rapidly bactericidal than vancomycin Infections caused by grampositive bacteria including sepsis and endocarditis IV administration renal clearance (half-life 8 h) dosed once daily inactivated by pulmonary surfactant so cannot be used to treat pneumonia Toxicity Myopathy monitoring of weekly creatine phosphokinase levels recommended... 

Daptomycin (Cubicin) is unique in that this drug binds to the cell membrane of susceptible bacteria and depolarizes the cell. Loss of membrane polarity results in a general inhibition of cell function and subsequent death of the bacterium. This drug is used primarily to treat skin infections caused by certain staphylococcal, streptococcal, and enterococcal bacteria. Because of its unique mechanism of action, daptomycin may also be... 

The level of LPG also influences the susceptibility of an MRSA strain to other antibiotics. A transposition mutant defective in mprF was less susceptible to moenomycin, but more susceptible to oxacillin, methicillin and gentamicin.41 Recent studies have shown that DapR strains have increased ratios of LPG/ PG,42 or increased amounts of LPG in the outer leaflet of the membrane, thus increasing the surface positive charge.43 This indicates that the mutations have enhanced ability to couple lysine to PG or to flip LPG to the outer leaflet. Deletion of mprF increases susceptibility to daptomycin by about four-fold in S. aureus.43,44 Disruption of mprF in B. subtilis caused a two-fold reduction in daptomycin MIC.34... 

Daptomycin localises to the cell division septum in B. subtilis 34 it causes rapid cell death without lysis,48 causes the formation of aberrant cell wall septa48 and treats biofilms effectively in S. aureus. 9 Daptomycin induces the cell wall stress stimulon in S. aureus and B. subtilis,30 34 but has very poor activity (MIC of 128) against an E. coli imp mutant defective in outer membrane assembly,5 whereas vancomycin, another bulky peptide that normally does not penetrate the outer membrane, has an MIC of 0.8 against E. coli imp.50... 

Daptomycin is a lipopeptide that binds to bacterial membranes and canses a rapid depolarization of membrane potential, which inhibits protein, DNA, and RNA synthesis, resulting in bacterial cell death. Daptomycin is indicated in treatment of complicated skin and skin structure infections caused by susceptible strains of Gram-positive microorganisms. 

Daptomycin binds to bacterial membranes resulting in depolarization, loss of membrane potential, and cell death. It has concentration-dependent bactericidal activity. Due to its unique mechanism of action, cross-resistance with other antibiotic classes seems not to occur, and there are no known resistance mechanisms. There were two cases (one S. aureus and the other E. faecalis) among more than 1000 cases treated in which resistance emerged during therapy. Staphylococci with decreased susceptibility to vancomycin have higher daptomycin MICs than fully susceptible strains. 

Daptomycin is a fermentation product having a cyclic lipopeptide structure. It is primarily active against Gram-positive infections, especially those involved in skin/skin structure infections. It is given IV but must be administered over a period of 30 minutes or more. It binds to cell membranes and causes depolarization, which interrupts protein, DNA, and RNA synthesis. Daptomycin is bactericidal. Although resistance can be achieved in vitro, resistance has been slow to emerge in the clinic. Patients should be monitored for muscle pain or weakness, because some incidence of elevated serum creatinine phosphokinase is associated with its use. A small number of clinical trial patients also developed conditions related to decreases in nerve conduction (e.g., paresthesias and Bell s palsy). Daptomycin is eliminated primarily by the kidney, so dose adjustment may be necessary in cases of renal insufficiency. 

Daptomycin was originally isolated from the soil saprotroph Streptomyces roseos-porus by scientists at Eli Lilly and Company in the 1980s. It is a novel lipopeptide antibiotic used in the treatment of certain infections caused by Gram-positive organisms. The proposed mechanism of action involves insertion of the lipophilic daptomycin tail into the bacterial cell membrane, causing rapid membrane depolarization and a potassium ion efflux. This leads to the arrest of DNA, RNA, and protein synthesis, resulting in bacterial cell death (see footnote 1). 

If the primary mechanism of daptomycin bactericidal activity is dissipation of membrane function that indirectly influences peptidoglycan, C A, RHA, protein, lipid, and teichoic acid biosynthesis, it is not clear why daptomycin is synergistic with aminoglycosides. Uptake and bactericidal activity of aminoglycosides require membrane potential (72,73). 

Canepari et al. (74) have shown that at the MIC, daptomycin caused only partial blockage of DNA, RNA, protein, and peptidoglycan biosynthesis in . faecium. In contrast, it caused >50% inhibition of radiolabeled phosphate into teichoic acid and >90% inhibition of incorporation of radiolabeled glycerol into lipoteichoic acid in 20 min in both S. aureus and in . faecium. They also showed that daptomycin does not penetrate bacterial cells, but binds reversibly to cell walls and irreversibly to cell membrane in the... 

In another study, Boaretti et al, (75) have shown that daptomycin at the MIC in the presence of causes inhibition of protoplast regeneration in H. faedum, whereas vancomycin does not. They showed that daptomycin caused 82% inhibition of lipotei-choic acid biosynthesis in E. faedum protoplasts, 40% inhibition of lipid biosynthesis, and only 14, 17, and 23% inhibition of peptidoglycan, DNA, and protein biosynthesis, respectively. They demonstrated Ca -dependent tight binding of daptomycin to the cytoplasmic membrane. These data are consistent with the notion that lipoteichoic acid biosynthesis is the primary target of daptomycin at low concentrations. 

Allen NE, Albom WE, Hobbs JN. Inhibition of membrane potential-depetKleni amitu> acid tiansport by daptomycin. Antimicrob Agent Chemother 1991 35 2639-2642. 

Boaretti M, Canepari P. identtftcarion of daptomycin-binding proteins in the membrane of Emerococeiis hirae. Antimicrob Agent Chemother 1995 39 2068-2072. 

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