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Raf-kinase inhibitor GW5074 shows antibacterial activity against methicillin-resistant Staphylococcus aureus and potentiates the activity of gentamicin.

ABSTRACT: Increasing antimicrobial resistance has compromised the effectiveness of many antibiotics, including those used to treat staphylococcal infections like methicillin-resistant Staphylococcus aureus. The development of combination therapies, where antimicrobial agents are used with compounds that inhibit resistance pathways is a promising strategy. Results/methodology: The Raf kinase inhibitor GW5074 exhibited selective in vitro activity against Gram-positive bacteria, including clinical isolates of S. aureus with a minimum inhibitory concentration (MIC) of 2-8 µg/ml. GW5074 was effective in vivo in the Galleria mellonella infection model. The compound showed synergy with gentamicin by lowering MIC by fourfold, compared with gentamicin MIC alone.This work demonstrates the antimicrobial properties of GW5074 and supports further investigation of the kinase inhibitors as antibiotic adjuvants.

SUBMITTER: Johnston T

PROVIDER: S-EPMC5619112 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Raf-kinase inhibitor GW5074 shows antibacterial activity against methicillin-resistant Staphylococcus aureus and potentiates the activity of gentamicin.

Johnston Tatiana T Hendricks Gabriel Lambert GL Shen Steven S Chen Roy Fangxing RF Kwon Bumsup B Kelso Michael John MJ Kim Wooseong W Burgwyn Fuchs Beth B Mylonakis Eleftherios E

Future medicinal chemistry 20160921 16

<h4>Aim</h4>Increasing antimicrobial resistance has compromised the effectiveness of many antibiotics, including those used to treat staphylococcal infections like methicillin-resistant Staphylococcus aureus. The development of combination therapies, where antimicrobial agents are used with compounds that inhibit resistance pathways is a promising strategy. Results/methodology: The Raf kinase inhibitor GW5074 exhibited selective in vitro activity against Gram-positive bacteria, including clinica ...[more]

PMID: 27652456

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Project description:Diabetic foot infection (DFI) is a common complication in diabetes patients, with foot infections being the leading cause of amputations. Staphylococcus aureus is frequently found in diabetic foot infections, of which methicillin-resistant Staphylococcus aureus (MRSA) has become a major clinical and epidemiological challenge. Since MRSA strains are resistant to most β-lactam antibiotics, and also partially resistant to other antibiotics, treatment is difficult and costly. The emergence of drug-resistant bacteria often arises from overuse or misuse of antibiotics. Clinically, canagliflozin is commonly used for the treatment of type 2 diabetes. On this basis, we investigated the antibacterial activity and mechanism of canagliflozin against MRSA, with the aim to discover novel functions of canagliflozin and provide new insights for the treatment of MRSA. Using the microbroth dilution method to determine the half maximal inhibitory concentration of drugs, we found that canagliflozin not only can inhibit the growth of methicillin-sensitive Staphylococcus aureus (MSSA) but also exhibits antibacterial activity against MRSA. The IC50 values, at approximately 56.01 μM and 57.60 μM, were almost the same. At 12 h, canagliflozin showed a significant antibacterial effect against MRSA at and above 30 μM. In addition, its combined use with penicillin achieved better antibacterial effects, which were increased by about three times. Additive antibacterial activity (FICI = 0.69) was found between penicillin and canagliflozin, which was better than that of doxycycline and canagliflozin (FICI = 0.95). Canagliflozin also affected bacterial metabolic markers, such as glucose, ATP, and lactic acid. The results of crystal violet staining indicate that canagliflozin disrupted the formation of bacterial biofilm. Our electron microscopy results showed that canagliflozin distorted the bacterial cell wall. The results of RT-PCR suggest that canagliflozin down-regulated the expressions of biofilm-related gene (clfA, cna, agrC, mgrA, hld) and methicillin-resistance gene (mecA), which was related to MRSA. Molecular docking also indicated that canagliflozin affected some interesting targets of MRSA, such as the sarA, crtM and fnbA proteins. In conclusion, canagliflozin exhibits antibacterial activity against MRSA by affecting bacterial metabolism, inhibiting its biofilm formation, distorting the bacterial cell wall, and altering the gene expression of biofilm formation and its virulence. Our study reveals the antibacterial activity of canagliflozin against MRSA, providing a new reference for treating diabetic foot infections.

Dataset Information

Raf-kinase inhibitor GW5074 shows antibacterial activity against methicillin-resistant Staphylococcus aureus and potentiates the activity of gentamicin.

Publications

Raf-kinase inhibitor GW5074 shows antibacterial activity against methicillin-resistant Staphylococcus aureus and potentiates the activity of gentamicin.

Similar Datasets

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