Diminished Macrophage Inflammatory Response to
            <i>Staphylococcus aureus</i>
            Isolates Exposed to Daptomycin versus Vancomycin or Oxacillin

English, B. Keith; Maryniw, Erik M.; Talati, Ajay J.; Meals, Elizabeth

doi:10.1128/aac.01559-05

Cited by 37 publications

(36 citation statements)

References 14 publications

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“…In fact, considerable evidence suggests that rapid killing of the organisms by bactericidal antibiotics leads to an augmented, potentially harmful inflammatory response (47). We have recently reported that exposure of macrophages to S. aureus isolates in the presence of bactericidal antibiotics triggers the release of large amounts of TNF-␣ and NO (33). Using heat-killed S. aureus bacteria, we confirmed many observations made with purified bacterial components and demonstrated that Mkp-1 KO mice are more vulnerable to septic shock and multiorgan failure during Gram-positive bacterial infection (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…To mimic clinical Gram-positive bacterial infection, we infected WT and Mkp-1 Ϫ/Ϫ mice with a virulent strain of CA-MRSA isolated from a pediatric patient with vertebral osteomyelitis (33). Because this isolate is more virulent than S. aureus FDA 209P, we injected mice via the tail vein with a lower dose of bacteria (3.5 ϫ 10 6 CFU/g body weight).…”

Section: Mkp-1mentioning

confidence: 99%

“…S. aureus FDA 209P was purchased from American Type Culture Collection (ATCC) and grown at 37°C for 18 h in ATCC medium 117. The second strain of S. aureus was a virulent strain of CA-MRSA isolated from a pediatric patient with vertebral osteomyelitis (33). This strain of bacteria was cultured for 18 h in tryptic soy broth at 37°C.…”

Section: S Aureus Preparationmentioning

confidence: 99%

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Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Wang

Meng

Kuhlman

et al. 2007

The Journal of Immunology

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MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1−/− macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1−/− macrophages produced more proinflammatory cytokines such as TNF-α and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-α, IL-6, IL-10, and MIP-1α, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Section: Mkp-1mentioning

confidence: 99%

Section: S Aureus Preparationmentioning

confidence: 99%

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Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Wang

Meng

Kuhlman

et al. 2007

The Journal of Immunology

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“…Daptomycin possess other unique features, such as its ability to be bactericidal without being bacteriolytic [42] (thus reducing over-stimulation of the immune response by the release of bacterial elements and a prolonged postantibiotic effect) and an efficacy maintained in both the static and growth phases of bacteria [43].…”

Section: Daptomycin and Derivativesmentioning

confidence: 99%

Lipopeptides as anti-infectives: a practical perspective

et al. 2009

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Abstract:Lipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chemical modifications introduced to improve their activity.

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“…For example, daptomycin treatment of methicillin-resistant S. aureus-in- fected macrophages leads to a 50% reduction in the production of proinflammatory cytokines, such as tumor necrosis factor alpha, compared with vancomycin treatment (2). Similarly, the potential for a lessened inflammatory response compared to that for ceftriaxone has recently been observed in an experimental model of pneumococcal meningitis (3).…”

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confidence: 99%

Daptomycin Exerts Bactericidal Activity without Lysis of Staphylococcus aureus

Cotroneo

Harris

Perlmutter³

et al. 2008

Antimicrob Agents Chemother

118

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The ability of daptomycin to produce bactericidal activity against Staphylococcus aureus while causing negligible cell lysis has been demonstrated using electron microscopy and the membrane integrity probes calcein and ToPro3. The formation of aberrant septa on the cell wall, suggestive of impairment of the cell division machinery, was also observed.Many antibiotics derive bactericidal activity from their ability to lyse cells, which may cause liberation of potent proinflammatory bacterial components, resulting in the generation of a robust innate immune response that can potentially cause harm to the host (8). The lipopeptide antibiotic daptomycin is active against a wide range of gram-positive bacteria (Cubicin prescription information, 2005; Cubist Pharmaceuticals, Lexington, MA) (4) and is believed to possess a novel mechanism of action that does not involve cell lysis. Instead, the lipophilic acyl tail of daptomycin is inserted into the cytoplasmic membrane of the bacterium, leading to potassium efflux; destruction of the ion-concentration gradient; membrane depolarization; inhibition of protein, DNA, and RNA synthesis; and finally cell death (Cubicin prescription information, 2005; Cubist Pharmaceuticals, Lexington, MA) (5, 11, 13). Daptomycin is rapidly bactericidal in vitro against Staphylococcus aureus at low multiples of the MIC (12). Here, we demonstrate the bactericidal activity of daptomycin against S. aureus in the absence of cell lysis. (Portions of this work were presented previously at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy [10].)Cell lysis was initially monitored by measuring optical density during log-phase time kills. Late-exponential-phase cultures (approximately 10 8 CFU/ml) were used to allow samples to be obtained for transmission electron microscopy (TEM). Staphylococcus aureus ATCC 29213 was grown overnight in calcium-supplemented Mueller-Hinton broth (MHBc; 50 mg/ liter Ca 2ϩ ) and subcultured 1:1,000 into fresh MHBc. Cultures were grown at 37°C with shaking (200 rpm) to an optical density at 600 nm (OD 600 ) of 0.3 to ensure sufficient biomass for fixation and processing. Daptomycin was added at multiples (1ϫ to 8ϫ) of the MIC (0.5 g/ml). At the indicated time points, samples were removed, OD 600 and number of CFU/ml were measured as previously described (7), and cells were pelleted and resuspended in 1 ml MHBc plus 2.5% (vol/vol) glutaraldehyde. Glutaraldehyde-fixed samples were postfixed in 2.0% (wt/vol) osmium tetroxide, followed by en bloc staining with 2.0% (wt/vol) uranyl acetate. The cells were then dehydrated through an ethanol series and embedded in LR White resin. Samples were thin sectioned and stained by uranyl acetate; lead citrate TEM was performed using a LEO 912AB microscope under standard operating conditions at 100 kV, with a liquid nitrogen anticontaminator in place.As shown in Fig. 1, at 4 g/ml, daptomycin was rapidly bactericidal, producing a Ͼ1,000-fold decrease in viability in less than 120 min, with no concomitant drop in OD 6...

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Diminished Macrophage Inflammatory Response to Staphylococcus aureus Isolates Exposed to Daptomycin versus Vancomycin or Oxacillin

Cited by 37 publications

References 14 publications

Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Lipopeptides as anti-infectives: a practical perspective

Daptomycin Exerts Bactericidal Activity without Lysis of Staphylococcus aureus

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