Further Insights into the Mode of Action of the Lipoglycopeptide Telavancin through Global Gene Expression Studies

Song, Yang; Lunde, Christopher S.; Benton, Bret M.; Wilkinson, Brian J.

doi:10.1128/aac.05403-11

Cited by 32 publications

(32 citation statements)

References 51 publications

(88 reference statements)

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“…In contrast, the expression of the enterotoxin gene set7 decreased with OHM in LAC but not LAC⌬agr, and OHM had no effect on the expression of the saeR component of the SaeRS virulence regulator. Likewise, the transcription of genes involved in the stress response (asp23, crtM, and clpB) was not altered by OHM, suggesting that OHM does not induce a general stress response in LAC under the conditions tested (50)(51)(52)(53)(54). Among the metabolism genes examined, OHM had no significant effect on the transcription of the genes involved in electron transport (atpG and sdhA).…”

Section: Resultsmentioning

confidence: 87%

ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Daly

Elmore

Kavanaugh

et al. 2015

Antimicrob Agents Chemother

112

147

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d Antibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, as they may limit pathogenesis and increase bacterial susceptibility to host killing. Staphylococcus aureus is a major cause of invasive skin and soft tissue infections (SSTIs) in both the hospital and community settings, and it is also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by the accessory gene regulator (agr) controls virulence factor production essential for causing SSTIs. We recently identified -hydroxyemodin (OHM), a polyhydroxyanthraquinone isolated from solid-phase cultures of Penicillium restrictum, as a suppressor of QS and a compound sought for the further characterization of the mechanism of action. At concentrations that are nontoxic to eukaryotic cells and subinhibitory to bacterial growth, OHM prevented agr signaling by all four S. aureus agr alleles. OHM inhibited QS by direct binding to AgrA, the response regulator encoded by the agr operon, preventing the interaction of AgrA with the agr P2 promoter. Importantly, OHM was efficacious in a mouse model of S. aureus SSTI. Decreased dermonecrosis with OHM treatment was associated with enhanced bacterial clearance and reductions in inflammatory cytokine transcription and expression at the site of infection. Furthermore, OHM treatment enhanced the immune cell killing of S. aureus in vitro in an agr-dependent manner. These data suggest that bacterial disarmament through the suppression of S. aureus QS may bolster the host innate immune response and limit inflammation.

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Section: Resultsmentioning

confidence: 87%

ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Daly

Elmore

Kavanaugh

et al. 2015

Antimicrob Agents Chemother

112

147

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“…Transcriptional response studies have shown a strong induction of the VraSR regulon in response to telavancin treatment, as observed for brilacidin treatment and as expected from a cell wall synthesis inhibitor. Moreover, telavancin highly upregulated the BraDE and VraDE ABC transporters, which are regulated by the NsaSR TCS (61). While brilacidin, daptomycin, and LL16 treatments did cause a large upregulation of the NsaSR regulon, not all members of this regulon were equally affected, and vraD and vraE were significantly upregulated by LL16 treatment only (22-and 35-fold, respectively) (see Table S2 in the supplemental material).…”

Section: Discussionmentioning

confidence: 98%

“…However, only brilacidin and LL16 lead to a significant induction of the lysine biosynthesis pathway (Dap operon), while only brilacidin and daptomycin treatment upregulated cellular proteases and chaperones. The induction of the Dap operon as well as cytoplasmic chaperones/proteases in response to telavancin treatment was also observed (61) and is thought to be a hallmark of membrane The maximal upregulation at any time point under each given condition is reported. Genes with Ͼ3-fold maximal regulation are highlighted in boldface type and underlining.…”

Section: Discussionmentioning

confidence: 99%

Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

Mensa

Howell

Scott³

et al. 2014

Antimicrob Agents Chemother

150

145

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b Brilacidin (PMX30063) has shown potent bactericidal activity against drug-resistant and -susceptible strains of multiple Gramnegative and Gram-positive pathogens. In this study, we demonstrate that brilacidin causes membrane depolarization in the Gram-positive bacterium Staphylococcus aureus, to an extent comparable to that caused by the lipopeptidic drug daptomycin. Transcriptional profiling of Staphylococcus aureus by deep sequencing shows that the global response to brilacidin treatment is well correlated to those of treatment with daptomycin and the cationic antimicrobial peptide LL37 and mostly indicates abrogation of cell wall and membrane functions. Furthermore, the upregulation of various chaperones and proteases by brilacidin and daptomycin indicates that cytoplasmic protein misfolding stress may be a contributor to the mechanism of action of these drugs. These stress responses were orchestrated mainly by three two-component systems, GraSR, VraSR, and NsaSR, which have been implicated in virulence and drug resistance against other clinically available antibiotics. The recent rise of multidrug-resistant pathogenic bacteria is an alarming health care crisis that has outpaced the discovery of effective and novel therapeutics (1, 2). Antimicrobial peptides (AMPs), which are evolutionarily conserved, first-line host defense mechanisms, offer an attractive platform for the development of new antibiotics (3-5). Most AMPs are believed to interact with bacterial membranes and cause cell death by dysregulating the properties of the phospholipid bilayer or by causing membrane leakage, although some have been identified to have downstream cytoplasmic targets as well (6). Despite the variety of sequences and secondary and tertiary structures, most AMPs share an amphiphilic topology, with a charged, mostly positive face that allows for interaction with the negatively charged bacterial membrane and a hydrophobic face that allows for insertion into the membrane and interaction with the apolar acyl chains of the bilayer (4, 7-10). Several mechanisms have been suggested for the nature of this interaction with the membrane, including carpet, toroidal pore, and barrel stave mechanisms (6). Development of resistance to these peptides is limited (11), presumably due to the membrane being the primary target (12). As such, several strategies have been employed to mimic the activity of AMPs in order to improve efficacy, selectivity for bacteria, and bioavailability while circumventing issues associated with peptidic drugs, such as proteolytic degradation and difficulties with large-scale synthesis. These include the use of scaffolds such as D-L peptides, ␤-amino acid helices, and antimicrobial polymers (13-15).In previous work, we developed a series of small-molecule arylamide mimics of AMPs that showed potent activity against a broad range of drug-susceptible and multidrug-resistant Gramnegative and Gram-positive bacteria (15-19). These compounds feature a small arylamide backbone that is stabilized by intramolecular hydroge...

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“…Microarray analyses revealed that after 15 min of exposure to the drug a strong expression of the cell wall stress stimulon (characteristic response to inhibition of cell wall biosynthesis), which was accompanied after 60 min of exposure by an induction of various genes, was also affected by other membrane-depolarizing drugs [34]. These data support a dual mode of action and may explain the bimodal shape of concentration-effect relationships in killcurve experiments [35].…”

Section: Mechanism Of Action Of Lipoglycopeptidesmentioning

confidence: 67%

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

Bambeke

2015

Drugs

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Oritavancin, telavancin, and dalbavancin are recently marketed lipoglycopeptides that exhibit remarkable differences to conventional molecules. While dalbavancin inhibits the late stages of peptidoglycan synthesis by mainly impairing transglycosylase activity, oritavancin and telavancin anchor in the bacterial membrane by the lipophilic side chain linked to their disaccharidic moiety, disrupting membrane integrity and causing bacteriolysis. Oritavancin keeps activity against vancomycin-resistant enterocococci, being a stronger inhibitor of transpeptidase than of transglycosylase activity. These molecules have potent activity against Grampositive organisms, most notably staphylococci (including methicillin-resistant Staphylococcus aureus and to some extent vancomycin-intermediate S. aureus), streptococci (including multidrug-resistant pneumococci), and Clostridia. All agents are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin, for hospitalacquired and ventilator-associated bacterial pneumonia. While telavancin is administered daily at 10 mg/kg, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing (single dose of 1200 mg for oritavancin and 1000 mg at day 1 followed by 500 mg at day 8 for dalbavancin), which could be exploited in the future for outpatient therapy. Among possible safety issues evidenced during clinical development were an increased risk of developing osteomyelitis with oritavancin; taste disturbance, nephrotoxicity, and risk of corrected QT interval prolongation (especially in the presence of at-risk co-medications) with telavancin; and elevation of hepatic enzymes with dalbavancin. Interference with coagulation tests has been reported with oritavancin and telavancin. These drugs proved non-inferior to conventional treatments in clinical trials but their advantages may be better evidenced upon future evaluation in more severe infections. Key PointsNew lipoglycopeptides (telavancin, oritavancin, dalbavancin) differ from vancomycin by the presence of a lipophilic side chain, which profoundly modifies their pharmacokinetic and/or pharmacodynamic profile.Among these agents, telavancin and oritavancin have multiple modes of action and are highly bactericidal.Oritavancin and dalbavancin have prolonged halflives, allowing for their use a single-dose or twodose (once-a-week) regimen, respectively. These three drugs are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin is indicated for hospital-acquired and ventilator-associated bacterial pneumonia.

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Further Insights into the Mode of Action of the Lipoglycopeptide Telavancin through Global Gene Expression Studies

Cited by 32 publications

References 51 publications

ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

ω-Hydroxyemodin Limits Staphylococcus aureus Quorum Sensing-Mediated Pathogenesis and Inflammation

Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

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