SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance

Chieh Hsien Lu, Chung Wai Shiau, Yung Chi Chang, Hsiu Ni Kung, Jui Ching Wu, Chui Hian Lim, Hui Hui Yeo, Han Chu Chang, Han Sheng Chien, Sheng Hsuan Huang, Wei Kang Hung, Jun Rong Wei, Hao Chieh Chiu*

*此作品的通信作者

研究成果: Review article同行評審

8 引文 斯高帕斯(Scopus)

摘要

Objectives: In the past few decades, multiple-antibiotic-resistant Staphylococcus aureus has emerged and quickly spread in hospitals and communities worldwide. Additionally, the formation of antibiotic-tolerant persisters and biofilms further reduces treatment efficacy. Previously, we identified a sorafenib derivative, SC5005, with bactericidal activity against MRSA in vitro and in vivo. Here, we sought to elucidate the resistance status, mode of action and anti-persister activity of this compound. Methods: The propensity of S. aureus to develop SC5005 resistance was evaluated by assessment of spontaneous resistance and by multi-passage selection. The mode of action of SC5005 was investigated using macromolecular synthesis, LIVE/DEAD and ATPlite assays and DiOC2(3) staining. The effect of SC5005 on the mammalian cytoplasmic membrane was measured using haemolytic and lactate dehydrogenase (LDH) assays and flow cytometry. Results: SC5005 depolarized and permeabilized the bacterial cytoplasmic membrane, leading to reduced ATP production. Because of this mode of action, no resistance of S. aureus to SC5005 was observed after constant exposure to sub-lethal concentrations for 200 passages. The membrane-perturbing activity of SC5005 was specific to bacteria, as no significant haemolysis or release of LDH from human HT-29 cells was detected. Additionally, compared with other bactericidal antibiotics, SC5005 exhibited superior activity in eradicating both planktonic and biofilm-embedded S. aureus persisters. Conclusions: Because of its low propensity for resistance development and potent persister-eradicating activity, SC5005 is a promising lead compound for developing new therapies for biofilm-related infections caused by S. aureus.

原文English
頁(從 - 到)2049-2056
頁數8
期刊Journal of Antimicrobial Chemotherapy
76
發行號8
DOIs
出版狀態Published - 1 8月 2021

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