Insights into the antimicrobial effects of ceritinib against Staphylococcus aureus in vitro and in vivo by cell membrane disruption

Abstract

According to a 2019 report from the Centers of Disease Control and Prevention (CDC), methicillin-resistant Staphylococcus aureus (MRSA) was listed as one of the “serious threats” that had become a global public challenge in hospitals and community. Biofilm-associated infections and refractory persisters of S. aureus also impede the effectiveness of conventional antibiotics that have greatly increased difficulty in clinical therapy. There is an urgent need to develop new antimicrobials with antibiofilm and anti-persister capacities, and drug repurposing is the most effective and most economical solution to the problem. The present study profiles the antimicrobial activity of ceritinib, a tyrosine kinase inhibitor, against S. aureus in vitro and in vivo. We investigated the antimicrobial efficacy of ceritinib against planktonic and persistent S. aureus by a time-killing kinetics assay. Then, antibiofilm effect of ceritinib was assessed by crystal violet staining and laser confocal microscope observation. Ceritinib showed biofilm inhibition and mature biofilm eradication, and possesses robust bactericidal activity against S. aureus persisters. We also evaluated antimicrobial efficacy in vivo using a subcutaneous abscess infection model. Ceritinib ameliorated infection in a subcutaneous abscess mouse model and only showed negligible systemic toxicity in vivo. Mechanism exploration was conducted by transmission electron microscopy, fluorescently labeled giant unilamellar vesicle assays, and a series of fluorescent dyes. In conclusion, we find ceritinib represents potential bactericidal activity against MRSA by disrupting cell membrane integrity and inducing reactive oxygen species production, suggesting ceritinib has the potential to treat MRSA-related infections.

Repurposing of the antimalarial agent tafenoquine to combat MRSA

“…For the second screening procedure, the compound concentration was set as 50 µM and six hits were selected after removing the well-studied antimicrobials. After determining the MICs and MBCs of these candidates, TAF was ultimately selected for further study ( 23 ).…”

“…Fluorescence intensity was measured every 30 s for a total of 5 min with the λ ex and λ em of 622 and 670 nm, respectively. Melittin and 1% (vol/vol) DMSO were used as positive and negative controls, respectively ( 23 ).…”

Characterization of a Novel Antimicrobial Peptide Bacipeptin against Foodborne Pathogens

“…The reactive oxygen species (ROS) levels in MRSA cells were tested with the 2′,7′dichlorodihydrofluorescein diacetate (DCFH-DA, Solarbio, Beijing, China) fluorescence probe according to a previous method. 28 Briefly, overnight culture of MRSA CCARM 3090 was diluted with PBS to OD 600 of 0.3 and then incubated with 10 μM DCFH-DA in the absence of light at 37 °C for 45 min. The bacterial suspension was washed with PBS twice and then a different concentration of antimicrobial agent was added.…”

Utilization of Existing Human Kinase Inhibitors as Scaffolds in the Development of New Antimicrobials

“…Another HumKI having the amimopyrimidine moiety that has been evaluated for its antimicrobial activity against S. aureus [ 22 ] is Ceritinib (compound 7 ; Table 1 ), a tyrosine kinase inhibitor used in cancer treatment to inhibit anaplastic lymphoma kinase (ALK). The biochemical evaluation of Ceritinib against both Gram (−) and Gram (+) bacteria was based on a high throughput screen(s).…”

“…The biochemical evaluation of Ceritinib against both Gram (−) and Gram (+) bacteria was based on a high throughput screen(s). Ceritinib demonstrated antimicrobial activity only against Gram (+) bacteria, with the best activity against S. aureus laboratory and clinical MRSA and MSSA isolates (MICs and MBCs of 8–16 μg/mL and 8–64 μg/mL, respectively) [ 22 ]. Further examination of Ceritinib’s activity against biofilm formation showed significant biofilm mass reduction (of more than 2 log10 at 32 μg/mL) as well as eradication of the preformed biofilm.…”