Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis

Kwon, Hyuk‐Kwon; Yu, Kristin E.; Cahill, Sean V.; Alder, Kareme D.; Dussik, Christopher M.; Kim, Sanghun; Sharma, Lokesh; Back, Jungho; Oh, Irvin; Lee, Francis Y.

doi:10.15252/emmm.202115284

Cited by 8 publications

(3 citation statements)

References 54 publications

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“…However, other fumarate derivatives, including monomethyl fumarate and dimethyl fumarate, did not induce antibiotic persistence, despite their significant immunomodulatory properties. This is in line with some studies that dimethyl fumarate can be employed as an antibiotic adjuvant to effectively treat S. aureus persistent infections, due to the antagonistic effect on GAPDH and downregulation of glycolysis [31,42,43]. Whereas, monomethyl fumarate has been reported to have the function of driving innate immunity and inducing trained immunity [30,44].…”

Section: Plos Pathogenssupporting

confidence: 87%

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence

Lin,

Liu,

Zhou

et al. 2024

PLoS Pathog

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Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.

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Section: Plos Pathogenssupporting

confidence: 87%

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence

Lin,

Liu,

Zhou

et al. 2024

PLoS Pathog

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“…The vancomycin group received 50 mg/kg, while the combination group received 50 mg/kg Mo-A and 50 mg/kg vancomycin. Subsequent subcutaneous injections were administered every 12 h, and survival was monitored at 12 h intervals for up to 96 h 61 , 62 .…”

Section: Methodsmentioning

confidence: 99%

Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus

Guo,

Wang,

Zhang

et al. 2024

npj Biofilms Microbiomes

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Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets—becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.

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“…DM also predisposes patients to infection, which can be devastating to the diabetic bone fracture healing response ( Carey et al., 2018 ). The most common causative agent of musculoskeletal infection is Staphylococcus aureus , and resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) pose an increased risk to recalcitrant osteomyelitis and septic arthritis ( Ellington et al., 2006 ; Calhoun et al., 2009 ; Garzoni and Kelley, 2009 ; Lindsey et al., 2010 ; de Mesy Bentley et al., 2017 ; Johnson et al., 2018 ; Johnson et al., 2019 ; Yu et al., 2020a ; Kwon et al., 2021 ; Kwon et al., 2022a ; Kwon et al., 2022b ; Yu et al., 2022 ; Kwon et al., 2023 ). Systemic antibiotics are a prerequisite for open fractures with highly suspicious bacterial contamination ( Burke, 1961 ; Gillespie and Walenkamp, 2001 ; Penn-Barwell et al., 2012 ; Carver et al., 2017 ; Sweet et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model

Kwon,

Cahill,

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionDiabetes mellitus (DM) impairs fracture healing and is associated with susceptibility to infection, which further inhibits fracture healing. While intermittent parathyroid hormone (1-34) (iPTH) effectively improves fracture healing, it is unknown whether infection-associated impaired fracture healing can be rescued with PTH (teriparatide).MethodsA chronic diet-induced type 2 diabetic mouse model was used to yield mice with decreased glucose tolerance and increased blood glucose levels compared to lean-fed controls. Methicillin-resistant Staphylococcus aureus (MRSA) was inoculated in a surgical tibia fracture model to simulate infected fracture, after which mice were treated with a combination of antibiotics and adjunctive teriparatide treatment. Fracture healing was assessed by Radiographic Union Scale in Tibial Fractures (RUST), micro-computed tomography (μCT), biomechanical testing, and histology.ResultsRUST score was significantly poorer in diabetic mice compared to their lean nondiabetic counterparts. There were concomitant reductions in micro-computed tomography (μCT) parameters of callus architecture including bone volume/total volume, trabecular thickness, and total mineral density in type 2 diabetes mellitus (T2DM) mice. Biomechanicaltesting of fractured femora demonstrated diminished torsional rigidity, stiffness, and toughness to max torque. Adjuvant teriparatide treatment with systemic antibiotic therapy improved numerous parameters of bone microarchitecture bone volume, increased connectivity density, and increased trabecular number in both the lean and T2DM group. Despite the observation that poor fracture healing in T2DM mice was further impaired by MRSA infection, adjuvant iPTH treatment significantly improved fracture healing compared to antibiotic treatment alone in infected T2DM fractures. DiscussionOur results suggest that teriparatide may constitute a viable adjuvant therapeutic agent to improve bony union and bone microarchitecture to prevent the development of septic nonunion under diabetic conditions.

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Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis

Cited by 8 publications

References 54 publications

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence

Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model

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