SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance
| Autor: | Han Chu Chang, Yung Chi Chang, Han Sheng Chien, Hao-Chieh Chiu, Hui Hui Yeo, Hsiu Ni Kung, Chung Wai Shiau, Jun Rong Wei, Chui Hian Lim, Wei Kang Hung, Jui Ching Wu, Sheng Hsuan Huang, Chieh Hsien Lu |
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| Rok vydání: | 2021 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
0301 basic medicine Microbiology (medical) Staphylococcus aureus medicine.drug_class 030106 microbiology Antibiotics Microbial Sensitivity Tests medicine.disease_cause Membrane Potentials Microbiology 03 medical and health sciences In vivo medicine Animals Humans Pharmacology (medical) Mode of action Pharmacology biology Chemistry Staphylococcal Infections Haemolysis biology.organism_classification medicine.disease Methicillin-resistant Staphylococcus aureus Hemolysis Anti-Bacterial Agents 030104 developmental biology Infectious Diseases Biofilms Bacteria |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 76:2049-2056 |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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