Figure 1 - uploaded by Grace M Thorne
Content may be subject to copyright.
Source publication
Infections caused by drug-resistant pathogens are on the rise. Daptomycin, a cyclic lipopeptide with activity against most Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, is a newly US-FDA approved antimicrobial for complicated skin and skin structure infections (cSSSI). Daptomyci...
Context in source publication
Similar publications
Daptomycin is a branched cyclic anionic lipopeptide antibiotic that was discovered in the early 1980's but got the FDA approval only in 2003. This novel pharmaceutical molecule has demonstrated great in vitro activity against a wide range of aerobic and anaerobic gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vanc...
Daptomycin is a lipopeptide with bactericidal activity that acts on the cell membrane of enterococci and is often used off-label to treat patients infected with vancomycin-resistant enterococci. However, the emergence of resistance to daptomycin during therapy threatens its usefulness.
We performed whole-genome sequencing and characterization of th...
![Fig. 3 The mode of action of Daptomycin [41].](profile/Subir-Kundu/publication/294482945/figure/fig1/AS:329255452987393@1455512025611/The-mode-of-action-of-Daptomycin-41_Q320.jpg)
The emergence of antimicrobial drugs is a breakthrough health intervention that has helped save millions of lives and reduces the morbidity of several infectious diseases. However, the concrete advances in control of infectious diseases need to tackle the parallel upsurge in resistance to antimicrobials. There has been an alarming situation in the...
Daptomycin, as a lipopeptide antibiotic, exhibits high potency in the treatment of infections caused by clinically relevant drug‐resistant Gram‐positive pathogens, such as methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococci. However, its bactericidal mechanism of action remains controversial. In this study, we report th...
Daptomycin is a lipopeptide antibiotic that is active against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). It is less nephrotoxic than vancomycin. It has a unique bactericidal mechanism through destruction of bacterial membrane potential. However, one of the most clinically relevant adverse effects...
Citations
... Daptomycin (DAP) is a lipopeptide antibiotic with broad activity against Grampositive bacteria. It is positively charged when complexed with its calcium cofactor and targets the negatively charged bacterial membrane wherein it oligomerizes to cause membrane disruption, ion leakage, and eventual cell death (Steenbergen et al., 2005;Taylor & Palmer, 2016). Daptomycin bactericidal activity is also conferred by its ability to disrupt fluid membrane microdomains during membrane insertion. ...
Daptomycin is a last‐line antibiotic commonly used to treat vancomycin‐resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPR acquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol‐modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPR in pathogens such as methicillin‐resistant Staphylococcus aureus. Since Enterococcus faecalis encodes two paralogs of mprF and clinical DAPR mutations do not map to mprF, we hypothesized that functional redundancy between the paralogs prevents mprF‐mediated resistance and masks other evolutionary pathways to DAPR. Here, we performed in vitro evolution to DAPR in mprF mutant background. We discovered that the absence of mprF results in slowed DAPR evolution and is associated with inactivating mutations in ftsH, resulting in the depletion of the chaperone repressor HrcA. We also report that ftsH is essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced extracellular acidification and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti‐resistance strategies.
... Antibiotic resistance in S. aureus may result in higher morbidity, mortality, lengths of hospitalization and health expenditures [1]. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) [2] is becoming a main resource in therapy against multidrug-resistant S. aureus, especially methicillin-resistant S. aureus (MRSA), due to its activity against glycopeptide and linezolid-resistant MRSA [3,4]. The mechanism of action of DAP differs from conventional glycopeptides (vancomycin, teicoplanin) and is more like the cationic antimicrobial peptides produced by the immune system. ...
Daptomycin is one of the last therapeutic resources for multidrug-resistant gram-positive bacteria. Despite its structural similarities with glycopeptides, its mechanisms of action and resistance are different and in some respects are not completely understood. Mutations in several genes have been associated with daptomycin resistance, especially in mprF, walkR, rpoB and rpoC, but their role and importance remain to be elucidated. We have studied mutations in 11 genes, which have been previously associated with daptomycin non-susceptibility, in nine daptomycin-non-susceptible Staphylococcus aureus clinical isolates (daptomycin MIC: >1 mg/L). Susceptibility to daptomycin, vancomycin, linezolid, oxacillin, telavancin and dalbavancin was studied. walkR, agrA, cls1, cls2, fakA, pnpA, clpP, prs, rpoB, rpoC and mprF were amplified by PCR and sequenced. The sequences were compared with the S. aureus ATCC 25923 complete genome (GenBank gi: 685631213) by using BLAST ® software. We did not find any changes in walkR, pnpA, prs and clpP. All isolates excepting isolate MSa5 showed a high number of significant mutations (between 13 and 25 amino acid changes) in mprF. Most isolates also showed mutations in the rpo genes, the cls genes and fakA. Daptomycin non-susceptibility in S. aureus clinical isolates seems to be reached through different mutation combinations when compared to S. aureus ATCC 25293. Especially mprF and cls1 showed very high polymorphism in most isolates. Meanwhile, one isolate, MSa5, showed only single mutation in mprF (P314T).
... Methicillin-resistant Staphylococcus aureus (MRSA) infections continued to be a significant public health challenge in the United States, with reported mortality ranging from 20% to 30% [1,2]. Vancomycin has been the first-line antibiotic for the treatment of MRSA infections, particularly bloodstream infections (BSIs) [3]. However, the available evidence demonstrates challenges regarding its safety profile as well as tissue penetration and slow killing time [4,5]. ...
Background
In the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs), vancomycin stands as the prevalent therapeutic agent. Daptomycin remains an alternative antibiotic to treat MRSA BSIs in cases where vancomycin proves ineffective. However, studies have conflicted on whether daptomycin is more effective than vancomycin among patients with MRSA BSI.
Objective
To compare the effectiveness of daptomycin and vancomycin for the prevention of mortality among adult patients with MRSA BSI.
Methods
Systematic searches of databases were performed, including Embase, PubMed, Web of Science, and Cochrane Library. The Newcastle Ottawa Scale (NOS) and Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) were used to assess the quality of individual observational and randomized control studies, respectively. Pooled odd ratios were calculated using random effects models.
Results
Twenty studies were included based on a priori set inclusion and exclusion criteria. Daptomycin treatment was associated with non-significant lower mortality odds, compared to vancomycin treatment (OR = 0.81; 95% CI, 0.62, 1.06). Sub-analyses based on the time patients were switched from another anti-MRSA treatment to daptomycin demonstrated that switching to daptomycin within 3 or 5 days was significantly associated with 55% and 45% decreased odds of all-cause mortality, respectively. However, switching to daptomycin any time after five days of treatment was not significantly associated with lower odds of mortality. Stratified analysis based on vancomycin minimum inhibitory concentration (MIC) revealed that daptomycin treatment among patients infected with MRSA strains with MIC≥1 mg/L was significantly associated with 40% lower odds of mortality compared to vancomycin treatment.
Conclusion
Compared with vancomycin, an early switch from vancomycin to daptomycin was significantly associated with lower odds of mortality. In contrast, switching to daptomycin at any time only showed a trend towards reduced mortality, with a non-significant association. Therefore, the efficacy of early daptomycin use over vancomycin against mortality among MRSA BSIs patients may add evidence to the existing literature in support of switching to daptomycin early over remaining on vancomycin. More randomized and prospective studies are needed to assess this association.
... Antibiotic resistance in S. aureus results in higher morbidity, mortality, length of hospitalization and health expenditure [1]. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) [2] is becoming a main resource in therapy against multidrug-resistant S. aureus, especially methicillin-resistant S. aureus (MRSA), due to its activity against glycopeptide and linezolid-resistant MRSA [3,4]. The mechanism of action of DAP differs from conventional glycopeptides (vancomycin, teicoplanin), and is more like cationic antimicrobial peptides produced by the immune system. ...
... In addition, vancomycin has other secondary actions, probably less important in the lysis of the microorganism, such as inhibition of RNA synthesis and alteration of wall permeability. 2 The action of DAP is based on binding to the bacterial cell membrane, through its hydrophobic end, in the presence of calcium ions [7][8][9]. This binding occurs both in exponential growth phase and stationary phase, causing membrane depolarization due to the loss of potassium ions from the cytoplasm [10]. ...
Daptomycin is one of the last therapeutic resources for multidrug-resistant gram- positive bacteria. Despite its structural similarities with glycopeptides, its mechanisms of action and resistance are different, and in some respects are not completely understood. Mutations in several genes have been associated to daptomycin resistance, especially in mprF, walkR, rpoB and rpoC, but their role and importance remain to be elucidated. We have studied mutations in 11 genes, which have been previously associated to daptomycin non- susceptibility, in 9 daptomycin non-susceptible Staphylococcus aureus clinical isolates (daptomycin MIC: > 1mg/L). Susceptibility to daptomycin, vancomycin, linezolid, oxacillin, telavancin and dalbavancin were studied. walkR, agrA, cls1, cls2, fakA, pnpA, clpP, prs, rpoB, rpoC and mprF were amplified by PCR and sequenced. The sequences were compared with the S. aureus ATCC 25923 complete genome (GenBank gi: 685631213) by using BLAST® software. We did not find any changes in walkR, pnpA, prs and clpP. All isolates excepting isolate 5 showed a high number of significant mutations (between 13 and 25 amino acid changes) in mprF. Most isolates also showed mutations in rpo genes, cls genes and fakA. Daptomycin non-susceptibility in S. aureus clinical isolates seems to be reached through different mutations combinations when compared to S. aureus ATCC 25293. Especially mprF and cls1 showed a very high polymorphism in most isolates. Meanwhile, one isolate, St5, showed only single mutation in mprF (P314T).
... Moreover, its increased use worldwide has led to a rising incidence of vancomycin-resistant S. aureus (VRSA) isolates [13]. Daptomycin, a lipopeptide antibiotic, is an alternative therapy to vancomycin and is used for the treatment of infections caused by Gram-positive bacteria [14,15]. Daptomycin has an off-label clinical use for BJI, and it requires monitoring as it causes adverse effects such as myopathy and rhabdomyolysis. ...
... Daptomycin has an off-label clinical use for BJI, and it requires monitoring as it causes adverse effects such as myopathy and rhabdomyolysis. In contrast, prolonged use may result in Clostridium difficile-associated diarrhea and pseudomembranous colitis [14,15]. Also, linezolid, a synthetic oxazolidinone antimicrobial, is an alternative to glycopeptides to treat serious infections due to resistant Gram-positive organisms [16,17]. ...
Bone and joint infections (BJI) require prolonged antimicrobial treatment, leading to lengthy hospitalizations, high costs, the risk of nosocomial infections, and the development of antimicrobial resistance. Dalbavancin is a novel semisynthetic lipoglycopeptide approved for the treatment of adults and children with acute bacterial skin and skin structure infections. This narrative review aims to summarize the characteristics of dalbavancin and the current scientific evidence regarding its clinical efficacy and safety in the treatment of BJI. A literature search until June 2023 was performed to identify all published research about the role of dalbavancin in the management of BJI. Due to its unique pharmacokinetics characterized by prolonged half-life, high bactericidal activity against most Gram-positive bacteria, a good safety profile, and high tissue penetration, dalbavancin can be a valuable alternative to the treatment of BJI. Clinical studies have shown its non-inferiority compared to conventional therapies in BJI, offering potent activity against key pathogens and an extended dosing interval that may shorten hospitalization. In conclusion, dalbavancin represents a promising treatment option for BJI with a favorable safety profile, but further research in both adults and particularly children, who are ideal candidates for long-acting antibiotics, is necessary to evaluate the role of dalbavancin in BJI.
... Daptomycin (DAP) is a cyclic lipopeptide antibiotic with potent bactericidal activity against most Grampositive organisms [5] and retains good activity against various antibiotic-resistant Gram-positive bacteria (including methicillin-resistant staphylococci [6] and glycopeptide-resistant enterococci [7]) commonly causing CRBSIs. DAP's proposed mechanism of action involves calcium-dependent insertion of its lipophilic tail into the bacterial cell membrane resulting in generation of ion-conducting channels that disrupt the functional integrity of the Grampositive membrane, causing release of intracellular potassium, membrane depolarization and subsequent cell death [5]. ...
... Daptomycin (DAP) is a cyclic lipopeptide antibiotic with potent bactericidal activity against most Grampositive organisms [5] and retains good activity against various antibiotic-resistant Gram-positive bacteria (including methicillin-resistant staphylococci [6] and glycopeptide-resistant enterococci [7]) commonly causing CRBSIs. DAP's proposed mechanism of action involves calcium-dependent insertion of its lipophilic tail into the bacterial cell membrane resulting in generation of ion-conducting channels that disrupt the functional integrity of the Grampositive membrane, causing release of intracellular potassium, membrane depolarization and subsequent cell death [5]. Importantly, due to this unique mechanism of action, DAP does not appear to require bacterial cell division or active metabolism for bactericidal activity [8], which is very important when targeting biofilm-embedded bacteria. ...
Aim: To review preclinical and clinical data relevant to daptomycin lock therapy in catheter-related bloodstream infection (CRBSI). Methods: Systematic review in PubMed, Scopus and clinical trial registries. Results: Preclinical data demonstrate daptomycin lock solution stability and compatibility with heparin, good biofilm penetration, bactericidal activity against biofilm-embedded bacteria, and high efficacy in vitro and in animal catheter infection models. Clinical data remain limited (two case reports and five case series totaling n = 65 CRBSI episodes), albeit promising (successful catheter salvage in about 80% of cases). Conclusion: Despite theoretical advantages of daptomycin, clinical data remain scarce. Comparative studies versus alternative lock solutions are needed, as well as studies to define optimal daptomycin lock regimen (including optimal concentration, dwell time and lock duration).
... More recently, Reichard, et al. [36] analyzed this and several other drug stability studies and concluded the probability for failure of active pharmaceutical ingredients is greater in LEO, but also suggested that suitable protective repackaging strategies can help alleviate this problem. A second, and potentially greater, concern is that daptomycin is regarded as a last-resort option to treat multidrug-resistant pathogens and their infections [37]. As such, to reduce the chances for daptomycin resistance to spread, its use should be limited to only those cases where other options are not available. ...
In a survey of the International Space Station (ISS), the most common pathogenic bacterium identified in samples from the air, water and surfaces was Staphylococcus aureus. While growth under microgravity is known to cause physiological changes in microbial pathogens, including shifts in antibacterial sensitivity, its impact on S. aureus is not well understood. Using high-aspect ratio vessels (HARVs) to generate simulated microgravity (SMG) conditions in the lab, we found S. aureus lipid profiles are altered significantly, with a higher presence of branch-chained fatty acids (BCFAs) (14.8% to 35.4%) with a concomitant reduction (41.3% to 31.4%) in straight-chain fatty acids (SCFAs) under SMG. This shift significantly increased the sensitivity of this pathogen to daptomycin, a membrane-acting antibiotic, leading to 12.1-fold better killing under SMG. Comparative assays with two additional compounds, i.e., SDS and violacein, confirmed S. aureus is more susceptible to membrane-disrupting agents, with 0.04% SDS and 0.6 mg/L violacein resulting in 22.9- and 12.8-fold better killing in SMG than normal gravity, respectively. As humankind seeks to establish permanent colonies in space, these results demonstrate the increased potency of membrane-active antibacterials to control the presence and spread of S. aureus, and potentially other pathogens.
... It acts by calcium-dependent depolarization of bacterial cell membrane causing a release of intracellular potassium and cell death. It is used to treat MRSA and vancomycin-resistant enterococcus (VRE) skin and soft tissue infections, infective endocarditis, osteoarticular infections, and bacteremia [4]. It is avoided in the treatment of bronchoalveolar pneumonia due to its inactivation by alveolar surfactant [5]. ...
Daptomycin is a bactericidal antibiotic used to treat methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). Eosinophilic pneumonia is an uncommon but significant adverse effect of daptomycin. We present two patients treated with daptomycin who subsequently developed eosinophilic pneumonia (EP).
... Lipidated peptides have been presented as antibiotics for years. For instance, polymyxin B [9] and daptomycin [10] are two FDA-approved lipo-cyclic peptides. While daptomycin only displays activity against Gram-positive bacteria, polymyxin B is only active for Gram-negative bacteria. ...
Antibiotic resistance is one of the most significant issues encountered in global health. There is an urgent demand for the development of a new generation of antibiotic agents combating the emergence of drug resistance. In this article, we reported the design of lipidated dendrimeric γ-AApeptides as a new class of antimicrobial agents. These AApeptides showed excellent potency and broad-spectrum activity against both Gram-positive bacteria and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The mechanistic studies revealed that the dendrimeric AApeptides could kill bacteria rapidly through the permeabilization of bacterial membranes, analogous to host-defense peptides (HDPs). These dendrimers also did not induce antibiotic resistance readily. The easy access to the synthesis, together with their potent and broad-spectrum activity, make these lipidated dendrimeric γ-AApeptides a new generation of antibacterial agents.
... Amongst the antibiotics whose action leads to the disruption of the bacterial cell membrane, there are: cyclic lipopeptide [39][40][41][42][43][44][45][46][47][48][49] and polymyxins [50][51][52][53][54][55][56][57][58][59][60][61][62][63] (Figure 2). ...
... Then, the Ca 2+ -daptomycin complex is inserted into the membrane and undergoes phosphatidylglycerol-dependent oligomerization. Together, these events lead to the formation of membrane channels, which, combined with the loss of membrane integrity, cause the leakage of ions, mainly potassium and sodium, and a decrease in the transmembrane potential [45][46][47][48][49]. As a result, membranerelated processes are disrupted, eventually causing bacterial cell death (Figure 2(1)). ...
Despite the undisputed development of medicine, antibiotics still serve as first-choice drugs for patients with infectious disorders. The widespread use of antibiotics results from a wide spectrum of their actions encompassing mechanisms responsible for: the inhibition of bacterial cell wall biosynthesis, the disruption of cell membrane integrity, the suppression of nucleic acids and/or proteins synthesis, as well as disturbances of metabolic processes. However, the widespread availability of antibiotics, accompanied by their overprescription, acts as a double-edged sword, since the overuse and/or misuse of antibiotics leads to a growing number of multidrug-resistant microbes. This, in turn, has recently emerged as a global public health challenge facing both clinicians and their patients. In addition to intrinsic resistance, bacteria can acquire resistance to particular antimicrobial agents through the transfer of genetic material conferring resistance. Amongst the most common bacterial resistance strategies are: drug target site changes, increased cell wall permeability to antibiotics, antibiotic inactivation, and efflux pumps. A better understanding of the interplay between the mechanisms of antibiotic actions and bacterial defense strategies against particular antimicrobial agents is crucial for developing new drugs or drug combinations. Herein, we provide a brief overview of the current nanomedicine-based strategies that aim to improve the efficacy of antibiotics.
