Flufenamic Acid, a Promising Agent for the Sensitization of Colistin-Resistant Gram-Negative Bacteria to Colistin

Zhang, Yi; Han, Yijia; Wang, Lingbo; Kong, Jingchun; Pan, Wei; Zhang, Xiaodong; Chen, Lijiang; Yao, Zhuocheng; Zhou, Tieli; Cao, Jianming

doi:10.1128/spectrum.04052-22

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…We found that both DS and flufenac acid had a diphenylamine structure, and the combined effect of flufenac acid and colistin had been previously confirmed. 28 We suspect that this structure may play a role, which our team is currently investigating. Considering the future application, we have concerns regarding the antibacterial efficacy of DS in the human body.…”

Section: ■ Discussionmentioning

confidence: 97%

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin

Fu,

Liu,

et al. 2024

ACS Infect. Dis.

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The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.

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Section: ■ Discussionmentioning

confidence: 97%

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin

Fu,

Liu,

et al. 2024

ACS Infect. Dis.

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“…The cytotoxicity of Vero cells was detected by cell counting kit-8 (CCK-8) assay (Solarbio life sciences) based on previous report ( Zhang et al, 2023 ). The cells were plated in a 96-well plate at a density of 3 × 10 4 cells per well and treated with colistin (0.5, 1, 2, 4, 16, 32, 64 and 16 μg/mL) or the combination of colistin (0.5, 1, 2, 4, 16, 32, 64 and 16 μg/mL) and oxethazaine (20 μg/mL).…”

Section: Methodsmentioning

confidence: 99%

The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens

Li,

Han,

et al. 2024

Front. Pharmacol.

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Background:The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue.Methods:Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models.Results:In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models.Conclusion:These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.

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“…We based our methodology on previous reports, with minor modifications ( 24 ). Four COL-R A. baumannii and four COL-R E. coli isolates were randomly selected to evaluate the eradication effect of NTZ combined with COL on mature biofilms.…”

Section: Methodsmentioning

confidence: 99%

Antiparasitic nitazoxanide potentiates colistin against colistin-resistant Acinetobacter baumannii and Escherichia coli in vitro and in vivo

Xu,

Yao,

Kong

et al. 2024

Microbiol Spectr

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Multidrug-resistant Gram-negative bacterial infections pose a serious threat to public health and safety. Colistin is a line of defense against these infections, but colistin-resistant (COL-R) bacteria have emerged worldwide. This study aimed to explore the synergistic potential of nitazoxanide (NTZ) in combination with colistin for the treatment of COL-R Acinetobacter baumannii and Escherichia coli strains in vitro and in vivo . The checkerboard and time-killing assays indicated that NTZ in combination with colistin exhibited potent antibacterial activity against COL-R A. baumannii and COL-R E. coli . The antibiofilm activity measured by crystal violet staining and scanning electron microscopy combined with a confocal laser scanning microscope revealed that the combination of NTZ and colistin could inhibit biofilm formation and eradicate the formed biofilm. This study also demonstrated that the application of this drug combination to an in vivo infection model significantly increased the survival rate of Galleria mellonella larvae. Hemolysis tests revealed that the combination of NTZ and colistin showed no cytotoxicity. Altogether, the combination of NTZ and colistin showed promising synergistic antibacterial and antibiofilm effects in vitro and in vivo . This combination might be used as an alternative therapy for treating COL-R A. baumannii and COL-R E. coli infections. IMPORTANCE Colistin is used as a last resort in many infections caused by multidrug-resistant Gram-negative bacteria; however, colistin-resistant (COL-R) is on the rise. Hence, it is critical to develop new antimicrobial strategies to overcome COL-R. We found that nitazoxanide (NTZ) combined with colistin showed notable synergetic antibacterial activity. These findings suggest that the NTZ/colistin combination may provide an effective alternative route to combat COL-R A. baumannii and COL-R Escherichia coli infections.

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Flufenamic Acid, a Promising Agent for the Sensitization of Colistin-Resistant Gram-Negative Bacteria to Colistin

Abstract: Colistin is a last-line antibiotic used for the treatment of MDR Gram-negative bacterial infections. However, increasing resistance to it has been observed during clinical treatment.

Cited by 8 publications

References 46 publications

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin

The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens

Antiparasitic nitazoxanide potentiates colistin against colistin-resistant Acinetobacter baumannii and Escherichia coli in vitro and in vivo

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