Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus

Sweeney, Noreena L.; Lipker, Lauren; Hanson, Alicia M.; Bohl, Chris; Engel, Katie E.; Kalous, Kelsey S.; Stemper, Mary E.; Sem, Daniel S.; Schwan, William R.

doi:10.3390/antibiotics6010004

Cited by 12 publications

(6 citation statements)

References 26 publications

(31 reference statements)

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“…Pyrazolones are a biologically important group of compounds having diverse biological activities like antibacterial, antifungal, anti-inflammatory, antidiabetic, analgesic, antipyretic, immunosuppressive agents, hypoglycemic, antiviral, antineoplastic activity and other biological activities [155][156][157][158][159]. Although earlier many of pyrazolone derivatives were associated with adverse effects such as agranulocytosis, skin rashes, and blood dyscariasis, etc.…”

Section: Discussionmentioning

confidence: 99%

Approaches for Chemical Synthesis and Diverse Pharmacological Significance of Pyrazolone Derivatives: A Review

Asif

2021

J. Chil. Chem. Soc.

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Pyrazolone is a five-membered lactam ring containing two Nitrogens and one ketonic group in its structure. Numerous pyrazolone derivatives were exhibited with diverse biological, pharmacological, and chemical applications. When pyrazolones were discovered, they were only known as NSAIDs but in recent times they play a versatile role in several complications like cerebral ischemia, cardiovascular diseases, antibacterial, antioxidant, anticancer and several other pharmacological activities. Over the last few decades, pyrazolone derivatives have been used for various biochemical applications. Some of these derivatives such as metamizole, phenazone, aminopyrine, and propyphenazone, are widely used as anti-inflammatory and analgesics. The chemistry of pyrazolone has gained increasing attention due to its diverse pharmacological properties such as anticancer, analgesic, anti-inflammatory, antimicrobial, antioxidant, antifungal, antiviral, antidiabetic, and several other biological activities. Thus, keeping because of their importance, synthetic strategies for existing as well as novel pyrazolone derivatives have been developed and explored their biochemical utility. This review deals with the various pharmacological properties of different pyrazolone derivatives and puts chemical synthetic schemes.

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Section: Discussionmentioning

confidence: 99%

Approaches for Chemical Synthesis and Diverse Pharmacological Significance of Pyrazolone Derivatives: A Review

Asif

2021

J. Chil. Chem. Soc.

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“…The thioredoxin system is involved in many important physiological functions including cellular DNA synthesis, protein repair, cellular protein disulphide reduction, detoxification of reactive oxygen species, and regulation of transcription factor and cell death pathways. For these reasons, it has been an attractive target for anti‐tuberculous drugs . Thioredoxin system is essential for the survival of M tuberculosis under oxidative stress as M tuberculosis lack antioxidant glutathione reductase system .…”

Section: Discussionmentioning

confidence: 99%

“…For these reasons, it has been an attractive target for anti-tuberculous drugs. 25 Thioredoxin system is essential for the survival of M tuberculosis under oxidative stress as M tuberculosis lack antioxidant glutathione reductase system. 26,27 The genome of M tuberculosis encodes for three thioredoxins namely, thioredoxin A (Rv 1470), thioredoxin B (Rv 1471) and thioredoxin C (Rv 3914).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial antigens accumulation in foamy macrophages in murine pulmonary tuberculosis lesions: Association with necrosis and making of cavities

et al. 2020

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Understanding mechanisms of cavitation in tuberculosis (TB) is the missing link that could advance the field towards better control of the infection. Descriptions of human TB suggest that postprimary TB begins as lipid pneumonia of foamy macrophages that undergoes caseating necrosis and fragmentation to produce cavities. This study aimed to investigate the various mycobacterial antigens accumulating in foamy macrophages and their relation to tissue destruction and necrosis. Pulmonary tissues from mice with slowly progressive TB were studied for histopathology, acid‐fast bacilli (AFB) and presence of mycobacterial antigens. Digital quantification using Aperio ImageScope was done. Until week 12 postinfection, mice were healthy, and lesions were small with scarce AFB and mycobacterial antigens. Colony‐forming units (CFUs) increased exponentially. At week 16‐33, mice were sick, macrophages attained foamy appearance with an increase in antigens (P < .05), 1.5 log increase in CFUs and an approximately onefold increase in AFB. At week 37‐41, mice started dying with a shift in morphology towards necrosis. A >20‐fold increase in mycobacterial antigens was observed with only less than one log increase in CFUs and sevenfold increase in AFB. Secreted antigens were significantly (P < .05) higher compared to cell‐wall antigens throughout infection. Focal areas of necrosis were associated with an approximately 40‐fold increase in antigen MPT46, functionally active thioredoxin, and a significant increase in all secreted antigens. In conclusion, mycobacterial antigens accumulate in the foamy macrophages in TB lesions during slowly progressive murine pulmonary TB. Secreted antigens and MPT46 correlated with necrosis, thereby implying that they might trigger the formation of cavities.

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“…Inhibiting the bacterial thioredoxin reductase and disrupting the redox balance results in cell death (Bonilla et al, 2008; Debnath et al, 2012; Tejman-Yarden et al, 2013). This antibacterial drug target has been shown to highly limit the development of drug resistance (Lin et al, 2016; Sweeney et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Auranofin Releasing Antibacterial and Antibiofilm Polyurethane Intravascular Catheter Coatings

Liu

Shukla

Vera‐González

et al. 2019

Front. Cell. Infect. Microbiol.

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Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost and morbidity for patients but also in the over-consumption of medical resources for hospitals and health care organizations. In this study, a novel auranofin releasing antibacterial and antibiofilm polyurethane (PU) catheter coating was developed and investigated for future use in preventing CRBSIs. Auranofin is an antirheumatic drug with recently identified antimicrobial properties. The drug carrier, PU, acts as a barrier surrounding the antibacterial agent, auranofin, to extend the drug release profile and improve its long-term antibacterial and antibiofilm efficacy and potentially the length of catheter implantation within a patient. The PU+auranofin coatings developed here were found to be highly stretchable (exhibiting ~500% percent elongation), which is important for the compliance of the material on a flexible catheter. PU+auranofin coated catheters were able to inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) for 8 to 26 days depending on the specific drug concentration utilized during the dip coating process. The PU+auranofin coated catheters were also able to completely inhibit MRSA biofilm formation in vitro , an effect that was not observed with auranofin or PU alone. Lastly, these coatings were found to be hemocompatible with human erythrocytes and maintain liver cell viability.

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Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus

Cited by 12 publications

References 26 publications

Approaches for Chemical Synthesis and Diverse Pharmacological Significance of Pyrazolone Derivatives: A Review

Approaches for Chemical Synthesis and Diverse Pharmacological Significance of Pyrazolone Derivatives: A Review

Mycobacterial antigens accumulation in foamy macrophages in murine pulmonary tuberculosis lesions: Association with necrosis and making of cavities

Auranofin Releasing Antibacterial and Antibiofilm Polyurethane Intravascular Catheter Coatings

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