Many pathogenic species of bacteria are showing increasing drug resistance against clinically used antibiotics. Molecules structurally distant from known antibiotics and possessing membrane targeting bactericidal activities are more likely to display activity against drug-resistant pathogens. Mitocurcumin (MitoC) is one of such compounds, synthesized by triphenyl-phosphonium conjugation with curcumin, and has been shown recently from our laboratory to have broad-spectrum bactericidal activity (Kumari et al. 2019 Free Radic. Biol. Med. 143 140–145). Here, we further demonstrate the antibacterial properties of MitoC against resistant strains and also its mechanism of action. It displays efficient bactericidal activity against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae (MIC values in the 1.5–12.5 µM range), and coagulase-negative Staphylococci do not show resistance development against MitoC. Liposome based studies and MIC values against TolC deletion mutant (Δ tolC ; outer membrane protein) of E. coli suggest extensive membrane damage to be the primary mechanism of bactericidal activity. MitoC did not exhibit toxicity in BALB/c mice with an oral administration of 250 mg/kg body weight and was found to be totally safe without any significant effect on haematological, biochemical parameters and inflammatory responses. Its rapid bactericidal action as assessed by in vitro time-kill assay against B. subtilis , compared to ciprofloxacin, and long half-life in rodent serum, suggest that MitoC could be an excellent lead-molecule against drug-resistant pathogens. The highlights of the study are that mitocurcumin belongs to a structurally new class of bactericidal compounds. It displays activity against MDR strains of pathogenic bacteria and challenging MRSA. Liposome-based studies confirm the membrane damaging property of the molecule. Mitocurcumin does not show resistance development even after 27 bacterial generations.

中文翻译：

---

新型结构抗菌化合物三苯基鏻共轭二芳基庚烷的药理学表征：抗菌活性和分子机制

许多病原菌对临床使用的抗生素显示出越来越强的耐药性。在结构上远离已知抗生素并具有膜靶向杀菌活性的分子更有可能显示出针对耐药病原体的活性。丝裂姜黄素 (MitoC) 是此类化合物之一，由三苯基鏻与姜黄素共轭合成，最近我们的实验室已证明其具有广谱杀菌活性 (Kumari et al. 2019 Free Radic. Biol. Med. 143 140– 145)。在这里，我们进一步证明了 MitoC 对耐药菌株的抗菌特性及其作用机制。它对多重耐药的金黄色葡萄球菌和肺炎链球菌表现出有效的杀菌活性（MIC 值在 1.5-12.5 µM 范围内），和凝固酶阴性葡萄球菌不显示对 MitoC 的抗性发展。基于脂质体的研究和针对大肠杆菌的 TolC 缺失突变体（Δ tolC ；外膜蛋白）的 MIC 值表明广泛的膜损伤是杀菌活性的主要机制。MitoC 在口服 250 毫克/公斤体重的 BALB/c 小鼠中没有表现出毒性，并且被发现是完全安全的，对血液学、生化参数和炎症反应没有任何显着影响。与环丙沙星相比，通过对枯草芽孢杆菌的体外时间杀伤试验评估其快速杀菌作用，以及在啮齿动物血清中的长半衰期，表明 MitoC 可能是对抗耐药病原体的极好先导分子。该研究的亮点在于，丝裂姜黄素属于结构上新的一类杀菌化合物。它显示出抗 MDR 致病菌菌株和挑战 MRSA 的活性。基于脂质体的研究证实了该分子的膜破坏特性。即使经过 27 代细菌，丝裂姜黄素也没有表现出耐药性。