Role of bacterial components in macrophage activation by the LAC and MW2 strains of community-associated, methicillin-resistant Staphylococcus aureus

Spentzas, Thomas; Kudumula, Ravi; Acuña, Carlos; Talati, Ajay J.; Ingram, Kimberly C.; Savorgnan, Fabio; Meals, Elizabeth; English, B. Keith

doi:10.1016/j.cellimm.2011.03.009

Cited by 16 publications

(19 citation statements)

References 26 publications

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“…We measured secretion of other cytokines and found that IL-6 and IL-12 secretions were strongly correlated with TNF secretion in response to these bacteria ( r 2 = 0.92 and 0.91, resp.). These findings were consistent with our previous studies [9, 11]. We focused on TNF secretion for these studies.…”

Section: Methodssupporting

confidence: 93%

“…Concentrations were determined by colony counts. A range of concentrations of bacteria (10 5 –10 7 CFU/mL) was studied, based upon our previously published data with other CA-MRSA strains and our preliminary experiments [9–11]. The minimum inhibitory concentrations (MICs) for these strains were determined by using the E -test method in the microbiology laboratory at Le Bonheur Children's Hospital (LBCH).…”

Section: Methodsmentioning

confidence: 99%

“…TNF is a multifunctional cytokine that is produced primarily by activated macrophages and plays an important role in endotoxic shock, immunity, inflammation, antiviral responses, and diseases such as cachexia and non-insulin-dependent diabetes [6–8]. In our previous studies we showed that secretion of TNF depends on the expression of certain virulent factors, specifically four cytolytic phenol-soluble modulin (PSM) peptides [9]. The inflammatory response can be decreased in the presence of a nonlytic antibiotic, daptomycin [9, 10].…”

Section: Introductionmentioning

confidence: 99%

“…In our previous studies we showed that secretion of TNF depends on the expression of certain virulent factors, specifically four cytolytic phenol-soluble modulin (PSM) peptides [9]. The inflammatory response can be decreased in the presence of a nonlytic antibiotic, daptomycin [9, 10]. We also showed that one of most recommended anesthetics for septic shock, ketamine, can suppress the TNF secretion mechanism independently of PSM expression or nonlytic antibiotic action [11].…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages

Spentzas

Shappley

Savorgnan

et al. 2012

International Journal of Inflammation

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Background. Methicillin-resistant Staphylococcus aureus (MRSA) can stimulate massive cytokine release. Ketamine suppresses tumor necrosis factor (TNF) secretion by MRSA-stimulated RAW264.7 macrophages, and the mechanism likely involves N-methyl-D-aspartic acid (NMDA) receptor antagonism. The downstream effects of NMDA-mediated TNF suppression, specifically the PI3K/Akt and mTOR modulation, have not been described. Methods. RAW264.7 cells were stimulated for 18 hrs with 105 to 107 CFU/mL inocula of either of two prototypical community-acquired- (CA-) MRSA isolates, USA300 strain LAC and USA400 strain MW2. Then we added the NMDA inhibitors ketamine or 2R-amino-5-phosphonopentanoate (AP5), NMDA substrate, LY294002, and rapamycin in various combinations. Results. NMDA inhibition suppressed TNF secretion by almost a third compared to the no-ketamine control. When NMDA substrate was added, the TNF secretion increased by 10%. Addition of LY294002 suppressed TNF production by macrophages by 20%. Rapamycin exhibited a concentration-dependent TNF induction-suppression response: induction at doses of 0.1 and 1 ng/mL and suppression at 10 and 100 ng/mL. Induction of TNF was abolished when LY294002 was added and the suppression became uniform. Ketamine-induced suppression of TNF secretion was intensified 10–15% when rapamycin was added, but not when LY294002 was added. Conclusion. These findings suggest that NMDA-induced TNF suppression can be augmented by concurrent mTOR inhibition.

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Section: Methodssupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages

Spentzas

Shappley

Savorgnan

et al. 2012

International Journal of Inflammation

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“…The 2 hospital-associated MRSA (HA-MRSA) strains were from patients with persistent bacteremia derived from a multinational clinical trial collection [16,18,19]. The 2 community-associated MRSA (CA-MRSA) strains were MW2 (USA400, reported to cause fatal infection in children [13]) and JE2 (USA300 strain LAC, obtained from the National Institutes of Health Network on Antimicrobial Resistance in Staphylococcus aureus [NARSA] [17]). These MRSA strains belong to SCCmec type IV, in which strains are mecI and mecR2 negative and only have a truncated mecR1 [20].…”

Section: Bacterial Strains Plasmids and Growth Mediummentioning

confidence: 99%

The Global RegulonsarARegulates β-Lactam Antibiotic Resistance in Methicillin-ResistantStaphylococcus aureusIn Vitro and in Endovascular Infections

Cheung

Bayer

et al. 2016

J Infect Dis.

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Background. The global regulator sarA modulates virulence of methicillin-resistant Staphylococcus aureus (MRSA) via regulation of principal virulence factors (eg, adhesins and toxins) and biofilm formation. Resistance of S. aureus strains to β-lactam antibiotics (eg, oxacillin) depends on the production of penicillin-binding protein 2a (PBP2a), encoded by mecA.Methods. In the present study, we investigated the impact of sarA on the phenotypic and genotypic characteristics of oxacillin resistance both in vitro and in an experimental endocarditis model, using prototypic healthcare-and community-associated MRSA parental and their respective sarA mutant strain sets.Results. All sarA mutants (vs respective MRSA parental controls) displayed significant reductions in oxacillin resistance and biofilm formation in vitro and oxacillin persistence in an experimental endocarditis model in vivo. These phenotypes corresponded to reduced mecA expression and PBP2a production and an interdependency of sarA and sigB regulators. Moreover, RNA sequencing analyses showed that sarA mutants exhibited significantly increased levels of primary extracellular proteases and suppressed pyrimidine biosynthetic pathway, argininosuccinate lyase-encoding, and ABC transporter-related genes as compared to the parental strain.Conclusions. These results suggested that sarA regulates oxacillin resistance in mecA-positive MRSA. Thus, abrogation of this regulator represents an attractive and novel drug target to potentiate efficacy of existing antibiotic for MRSA therapy.

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Cinnamaldehyde targets SarA to enhance β‐lactam antibiotic activity against methicillin‐resistant Staphylococcus aureus

Li,

Lu,

Chu

et al. 2024

mLife

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Methicillin‐resistant Staphylococcus aureus (MRSA) is a current global public health problem due to its increasing resistance to the most recent antibiotic therapies. One critical approach is to develop ways to revitalize existing antibiotics. Here, we show that the phytogenic compound cinnamaldehyde (CIN) and β‐lactam antibiotic combinations can functionally synergize and resensitize clinical MRSA isolates to β‐lactam therapy and inhibit MRSA biofilm formation. Mechanistic studies indicated that the CIN potentiation effect on β‐lactams was primarily the result of inhibition of the mecA expression by targeting the staphylococcal accessory regulator sarA. CIN alone or in combination with β‐lactams decreased sarA gene expression and increased SarA protein phosphorylation that impaired SarA binding to the mecA promoter element and downregulated virulence genes such as those encoding biofilm, α‐hemolysin, and adhesin. Perturbation of SarA–mecA binding thus interfered with PBP2a biosynthesis and this decreased MRSA resistance to β‐lactams. Furthermore, CIN fully restored the anti‐MRSA activities of β‐lactam antibiotics in vivo in murine models of bacteremia and biofilm infections. Together, our results indicated that CIN acts as a β‐lactam adjuvant and can be applied as an alternative therapy to combat multidrug‐resistant MRSA infections.

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Role of bacterial components in macrophage activation by the LAC and MW2 strains of community-associated, methicillin-resistant Staphylococcus aureus

Cited by 16 publications

References 26 publications

Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages

Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages

The Global RegulonsarARegulates β-Lactam Antibiotic Resistance in Methicillin-ResistantStaphylococcus aureusIn Vitro and in Endovascular Infections

Cinnamaldehyde targets SarA to enhance β‐lactam antibiotic activity against methicillin‐resistant Staphylococcus aureus

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