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Antibacterial activity of Mn(I) and Re(I) tricarbonyl complexes conjugated to a bile acid carrier molecule.
Metallomics ( IF 3.4 ) Pub Date : 2020-08-20 , DOI: 10.1039/d0mt00142b Jono W Betts 1 , Patrick Roth 2 , Calum A Pattrick 3 , Hannah M Southam 3 , Roberto M La Ragione 1 , Robert K Poole 3 , Ulrich Schatzschneider 2
Metallomics ( IF 3.4 ) Pub Date : 2020-08-20 , DOI: 10.1039/d0mt00142b Jono W Betts 1 , Patrick Roth 2 , Calum A Pattrick 3 , Hannah M Southam 3 , Roberto M La Ragione 1 , Robert K Poole 3 , Ulrich Schatzschneider 2
Affiliation
A bifunctional cholic acid–bis(2-pyridylmethyl)amine (bpa) ligand featuring an amide linker was coordinated to a manganese(I) or rhenium(I) tricarbonyl moiety to give [M(bpacholamide)(CO)3] with M = Mn, Re in good yield and very high purity. Strong antibacterial activity was observed against four strains of methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, with minimum inhibitory concentrations (MICs) in the range of 2–3.5 μM. No difference in response was observed for the MSSA vs. MRSA strains. Activity was also independent of the nature of the metal center, as the Mn and Re complexes showed essentially identical MIC values. In contrast to some other metal carbonyl complexes, the activity seems to be unrelated to the release of carbon monoxide, as photoactivation of the Mn complex reduced the potency by a factor of 2–8. Both metal complexes were non-toxic in Galleria mellonella larvae at concentrations of up to 100× the MIC value. In vivo testing in Galleria larvae infected with MRSA/MSSA demonstrated a significant increase in overall survival rates from 46% in the control to 88% in the group treated with the metal complexes. ICP-MS analysis showed that the Mn and Re cholamide complexes are efficiently internalized by E. coli cells and do not interfere with membrane integrity, as evident from a lack of release of intracellular ATP. An increased sensitivity was observed in acrB, acrD, and mdt mutants that are defective in multidrug exporters, indicating that the compounds have an intracellular mechanism of action. Furthermore, E. coli mntP mutants defective in the gene encoding an Mn exporter were more sensitive than the wildtype, while inactivation of the regulator that controls expression of the Mn uptake proteins MntP and MntH slightly increased sensitivity to the compound. Single knockout mutants defective in genes linked to bile salt and oxidative stress response (dinF, yiaH, sodA, katE, and soxS) did not show increased sensitivity relative to the wild type. Overall, neither the cholic acid moiety nor the metal-carbonyl fragment alone appear to be responsible for the biological activity observed and thus the search for the primary intracellular target continues.
中文翻译:
Mn(I) 和 Re(I) 三羰基复合物与胆汁酸载体分子结合的抗菌活性。
双官能胆酸-双(2-吡啶基甲基)胺(BPA)的配体为特色的酰胺接头配位到锰(我)或铼(我)三羰基部分,得到[M(BPA cholamide)(CO)3 ]其中M = Mn、Re 收率良好且纯度非常高。对四株甲氧西林敏感 (MSSA) 和耐甲氧西林 (MRSA)金黄色葡萄球菌具有很强的抗菌活性,最小抑制浓度 (MIC) 范围为 2-3.5 μM。没有观察到 MSSA与MRSA 菌株。活性也与金属中心的性质无关,因为 Mn 和 Re 配合物显示出基本相同的 MIC 值。与其他一些金属羰基配合物相比,活性似乎与一氧化碳的释放无关,因为 Mn 配合物的光活化将效力降低了 2-8 倍。在高达 100 倍 MIC 值的浓度下,两种金属配合物在大蜡螟幼虫中均无毒。对感染 MRSA/MSSA 的Galleria幼虫进行的体内测试表明,总体存活率从对照组的 46% 显着增加到金属配合物处理组的 88%。ICP-MS 分析表明,Mn 和 Re 胆酰胺复合物通过以下方式有效内化大肠杆菌细胞不会干扰膜的完整性,这从细胞内 ATP 的释放不足就可以看出。在多药输出蛋白缺陷的acrB、acrD和mdt突变体中观察到敏感性增加,表明这些化合物具有细胞内作用机制。此外,在编码 Mn 输出蛋白的基因中存在缺陷的大肠杆菌 mntP突变体比野生型更敏感,而控制 Mn 摄取蛋白 MntP 和 MntH 表达的调节器的失活略微增加了对该化合物的敏感性。与胆汁盐和氧化应激反应相关的基因缺陷的单一敲除突变体(dinF , yiaH ,sodA、katE和soxS ) 没有表现出相对于野生型增加的敏感性。总体而言,胆酸部分和金属羰基片段似乎都不是观察到的生物活性的原因,因此继续寻找主要的细胞内靶标。
更新日期:2020-08-28
中文翻译:
Mn(I) 和 Re(I) 三羰基复合物与胆汁酸载体分子结合的抗菌活性。
双官能胆酸-双(2-吡啶基甲基)胺(BPA)的配体为特色的酰胺接头配位到锰(我)或铼(我)三羰基部分,得到[M(BPA cholamide)(CO)3 ]其中M = Mn、Re 收率良好且纯度非常高。对四株甲氧西林敏感 (MSSA) 和耐甲氧西林 (MRSA)金黄色葡萄球菌具有很强的抗菌活性,最小抑制浓度 (MIC) 范围为 2-3.5 μM。没有观察到 MSSA与MRSA 菌株。活性也与金属中心的性质无关,因为 Mn 和 Re 配合物显示出基本相同的 MIC 值。与其他一些金属羰基配合物相比,活性似乎与一氧化碳的释放无关,因为 Mn 配合物的光活化将效力降低了 2-8 倍。在高达 100 倍 MIC 值的浓度下,两种金属配合物在大蜡螟幼虫中均无毒。对感染 MRSA/MSSA 的Galleria幼虫进行的体内测试表明,总体存活率从对照组的 46% 显着增加到金属配合物处理组的 88%。ICP-MS 分析表明,Mn 和 Re 胆酰胺复合物通过以下方式有效内化大肠杆菌细胞不会干扰膜的完整性,这从细胞内 ATP 的释放不足就可以看出。在多药输出蛋白缺陷的acrB、acrD和mdt突变体中观察到敏感性增加,表明这些化合物具有细胞内作用机制。此外,在编码 Mn 输出蛋白的基因中存在缺陷的大肠杆菌 mntP突变体比野生型更敏感,而控制 Mn 摄取蛋白 MntP 和 MntH 表达的调节器的失活略微增加了对该化合物的敏感性。与胆汁盐和氧化应激反应相关的基因缺陷的单一敲除突变体(dinF , yiaH ,sodA、katE和soxS ) 没有表现出相对于野生型增加的敏感性。总体而言,胆酸部分和金属羰基片段似乎都不是观察到的生物活性的原因,因此继续寻找主要的细胞内靶标。