Discovery of fusidic acid derivatives as novel STING inhibitors for treatment of sepsis

Long, Junjun; Ying, Tianhao; Zhang, Lei; Yu, Tao; Wu, Jian; Liu, Yasen; Li, Xiaoli; You, Guoliang; Zhang, Leiming; Bi, Yi

doi:10.1016/j.ejmech.2022.114814

Cited by 8 publications

(3 citation statements)

References 41 publications

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“…Recently, Long et al synthesized a series of fusidic acid derivatives inhibiting the abnormal activation of STING-related pathways [ 108 ]. Based on molecular docking, compound 30 can interact directly with the residues of STING CTD, such as T263, G166, and R23.…”

Section: Sting Inhibitorsmentioning

confidence: 99%

Potential Therapeutic Value of the STING Inhibitors

2023

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The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases.

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Section: Sting Inhibitorsmentioning

confidence: 99%

Potential Therapeutic Value of the STING Inhibitors

2023

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“…The most active, Compound 30, was docked in the CDN-binding site of the STING PDB structure 4KSY, whereas the anti-inflammatory effect was tested in mouse models. Despite not being tested in human STING, Compound 30 would be a promising STING inhibitor [196].…”

Section: Small Organic Molecules As Drug Candidatesmentioning

confidence: 99%

The Many Ways to Deal with STING

Coderch

Arranz-Herrero

Pascual‐Teresa

et al. 2023

IJMS

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The stimulator of interferon genes (STING) is an adaptor protein involved in the activation of IFN-β and many other genes associated with the immune response activation in vertebrates. STING induction has gained attention from different angles such as the potential to trigger an early immune response against different signs of infection and cell damage, or to be used as an adjuvant in cancer immune treatments. Pharmacological control of aberrant STING activation can be used to mitigate the pathology of some autoimmune diseases. The STING structure has a well-defined ligand binding site that can harbor natural ligands such as specific purine cyclic di-nucleotides (CDN). In addition to a canonical stimulation by CDNs, other non-canonical stimuli have also been described, whose exact mechanism has not been well defined. Understanding the molecular insights underlying the activation of STING is important to realize the different angles that need to be considered when designing new STING-binding molecules as therapeutic drugs since STING acts as a versatile platform for immune modulators. This review analyzes the different determinants of STING regulation from the structural, molecular, and cell biology points of view.

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“…Fusidic acid (FA), a steroidal antibiotic, is commonly used for the treatment of staphylococcal infections, including skin, bone and joint infections [8][9][10]. The antibacterial mechanism of FA is based on its irreversible binding to the elongation factor G (EF-G) located on the ribosome [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Reversing the Natural Drug Resistance of Gram-Negative Bacteria to Fusidic Acid via Forming Drug–Phospholipid Complex

Liu,

Lai,

et al. 2024

Bioengineering

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Drug resistance substantially compromises antibiotic therapy and poses a serious threat to public health. Fusidic acid (FA) is commonly used to treat staphylococcal infections, such as pneumonia, osteomyelitis and skin infections. However, Gram-negative bacteria have natural resistance to FA, which is almost restrained in cell membranes due to the strong interactions between FA and phospholipids. Herein, we aim to utilize the strong FA–phospholipid interaction to pre-form a complex of FA with the exogenous phospholipid. The FA, in the form of an FA–phospholipid complex (FA-PC), no longer interacts with the endogenous membrane phospholipids and thus can be delivered into bacteria cells successfully. We found that the water solubility of FA (5 µg/mL) was improved to 133 µg/mL by forming the FA-PC (molar ratio 1:1). Furthermore, upon incubation for 6 h, the FA-PC (20 µg/mL) caused a 99.9% viability loss of E. coli and 99.1% loss of P. aeruginosa, while free FA did not work. The morphology of the elongated bacteria cells after treatment with the FA-PC was demonstrated by SEM. The successful intracellular delivery was shown by confocal laser scanning microscopy in the form of coumarin 6-PC (C6-PC), where C6 served as a fluorescent probe. Interestingly, the antibacterial effect of the FA-PC was significantly compromised by adding extra phospholipid in the medium, indicating that there may be a phospholipid-based transmembrane transport mechanism underlying the intracellular delivery of the FA-PC. This is the first report regarding FA-PC formation and its successful reversing of Gram-negative bacteria resistance to FA, and it provides a platform to reverse transmembrane delivery-related drug resistance. The ready availability of phospholipid and the simple preparation allow it to have great potential for clinical use.

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Discovery of fusidic acid derivatives as novel STING inhibitors for treatment of sepsis

Cited by 8 publications

References 41 publications

Potential Therapeutic Value of the STING Inhibitors

Potential Therapeutic Value of the STING Inhibitors

The Many Ways to Deal with STING

Reversing the Natural Drug Resistance of Gram-Negative Bacteria to Fusidic Acid via Forming Drug–Phospholipid Complex

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