The combination of cloxacillin, thioridazine and tetracycline protects mice against Staphylococcus aureus peritonitis by inhibiting α-Hemolysin-induced MAPK/NF-κB/NLRP3 activation.

Int J Biol Macromol

State Key Laboratory of Human-Animal Zoonotic infectious Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Department of Infectious Diseases, Department of Endocrinology, Department of Interventional Therapy of First Hospital of Jilin University, Changchun 130062, China. Electronic address:

Published: February 2022

Staphylococcus aureus (S. aureus) infection is difficult to fight, previous experimental reports have demonstrated thioridazine (TZ) and tetracycline (TC) is an inhibitor of S. aureus efflux pump NorA and autolysin Atl, respectively, here, by means of molecular docking and molecular dynamics simulation, we observed that thioridazine (TZ) and tetracycline (TC) blocked the binding of substrates to NorA and Atl, respectively, and reduced their activities, and our antibacterial susceptibility test and three-dimensional checkerboard method showed that the three-drug combination of antibiotic cloxacillin (CXN), TZ and TC had a synergistic anti-Staphylococcal activity in vitro, and α-Hemolysin tests and scanning electron microscopy showed that the three-drug combination and the subinhibitory concentration of the combination significantly inhibited the secretion of α-hemolysin relative to the number of membrane-derived vesicles produced by S. aureus. Whereas Western blot and pharmacological inhibition assays showed that the three-drug combination significantly inhibited the expression of MAPK/NF-κB/NLRP3 proteins in macrophages induced with S. aureus α-hemolysin. In vivo, the drug combination significantly reduced bacterial colony-forming unit counts in the viscera of a mouse peritonitis model of S. aureus infection, therapy reduced the primary inflammatory pathology and the bacteria-stimulated release of cytokines such as IL-1β and TNF-α, and inhibited the expression of MAPK/NF-κB/NLRP3 proteins in peritoneal macrophages. Thus, the combination of efflux pump inhibitor, autolysis inhibitor and antibiotic, is a novel anti-Staphylococcal and anti-inflammatory strategy who owning good antibacterial activity and significant inhibiting staphylococcal α-hemolysin and inflammation.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2021.12.112DOI Listing

Publication Analysis

Top Keywords

thioridazine tetracycline
12
three-drug combination
12
staphylococcus aureus
8
aureus infection
8
efflux pump
8
combination inhibited
8
inhibited expression
8
expression mapk/nf-κb/nlrp3
8
mapk/nf-κb/nlrp3 proteins
8
combination
7

Similar Publications

Unraveling antibiotic resistance mechanisms in Mycobacterium abscessus: the potential role of efflux pumps.

J Glob Antimicrob Resist

December 2022

Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.

Objectives: Mycobacterium abscessus is an opportunistic respiratory pathogen in patients with underlying lung disease. It is infamously known for its low treatment success rates because of its resistance to multiple classes of antibiotics. Further insight into M.

View Article and Find Full Text PDF

Photosensitizing drug reactions.

Clin Dermatol

February 2022

Department of Dermatology, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA.

Photosensitizing drug reactions are cutaneous eruptions that occur after exposure to ultraviolet radiation in patients using photosensitizing medications. The reactions can be broadly classified into phototoxic and photoallergic, with the former being much more common and well documented. There is an extensive list of photosensitizing medications, especially in the case of phototoxicity.

View Article and Find Full Text PDF

The combination of cloxacillin, thioridazine and tetracycline protects mice against Staphylococcus aureus peritonitis by inhibiting α-Hemolysin-induced MAPK/NF-κB/NLRP3 activation.

Int J Biol Macromol

February 2022

State Key Laboratory of Human-Animal Zoonotic infectious Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Department of Infectious Diseases, Department of Endocrinology, Department of Interventional Therapy of First Hospital of Jilin University, Changchun 130062, China. Electronic address:

Staphylococcus aureus (S. aureus) infection is difficult to fight, previous experimental reports have demonstrated thioridazine (TZ) and tetracycline (TC) is an inhibitor of S. aureus efflux pump NorA and autolysin Atl, respectively, here, by means of molecular docking and molecular dynamics simulation, we observed that thioridazine (TZ) and tetracycline (TC) blocked the binding of substrates to NorA and Atl, respectively, and reduced their activities, and our antibacterial susceptibility test and three-dimensional checkerboard method showed that the three-drug combination of antibiotic cloxacillin (CXN), TZ and TC had a synergistic anti-Staphylococcal activity in vitro, and α-Hemolysin tests and scanning electron microscopy showed that the three-drug combination and the subinhibitory concentration of the combination significantly inhibited the secretion of α-hemolysin relative to the number of membrane-derived vesicles produced by S.

View Article and Find Full Text PDF

Photosensitive drug eruptions are cutaneous adverse events due to exposure to a medication and either ultraviolet or visible radiation. In this review, the diagnosis, prevention and management of drug-induced photosensitivity is discussed. Diagnosis is based largely on the history of drug intake and the appearance of the eruption primarily affecting sun-exposed areas of the skin.

View Article and Find Full Text PDF

Reversing Antimicrobial Resistance in Multidrug-Resistant Klebsiella pneumoniae of Clinical Origin Using 1-(1-Naphthylmethyl)-Piperazine.

Microb Drug Resist

July 2018

1 School of Public Health, Physiotherapy and Sports Science, UCD Centre for Food Safety, University College Dublin, Dublin, Ireland .

Eleven clinical Klebsiella pneumoniae fluoroquinolone-resistant isolates were tested to access the potential of adjuvant therapies to reduce antimicrobial resistance using fixed concentrations of the chemosensitizers chlorpromazine (CPZ), thioridazine (TZ), phenylalanine-arginine-β-naphthylamide (PAβN), and 1-(1-naphthylmethyl)-piperazine-(NMP) with varying concentrations of antimicrobial agents nalidixic acid (NAL), ciprofloxacin (CIP), moxifloxacin (MXF), tetracycline (TET), and chloramphenicol (CHL). Ethidium bromide dye was used together with the chemosensitizers to investigate permeabilization effects. NMP was assessed for its capacity to reduce the mass of biofilm alone and in combination with CIP and MXF.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!