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Synergetic Antimicrobial Activity and Mechanism of Clotrimazole-Linked CO-Releasing Molecules
ACS Bio & Med Chem Au ( IF 3.8 ) Pub Date : 2022-04-08 , DOI: 10.1021/acsbiomedchemau.2c00007 Sofia S Mendes 1 , Joana Marques 1 , Edit Mesterházy 1 , Jan Straetener 2 , Melina Arts 3 , Teresa Pissarro 1 , Jorgina Reginold 1 , Anne Berscheid 2 , Jan Bornikoel 2 , Robert M Kluj 4 , Christoph Mayer 4 , Filipp Oesterhelt 2 , Sofia Friães 1 , Beatriz Royo 1 , Tanja Schneider 3 , Heike Brötz-Oesterhelt 2 , Carlos C Romão 1 , Lígia M Saraiva 1
ACS Bio & Med Chem Au ( IF 3.8 ) Pub Date : 2022-04-08 , DOI: 10.1021/acsbiomedchemau.2c00007 Sofia S Mendes 1 , Joana Marques 1 , Edit Mesterházy 1 , Jan Straetener 2 , Melina Arts 3 , Teresa Pissarro 1 , Jorgina Reginold 1 , Anne Berscheid 2 , Jan Bornikoel 2 , Robert M Kluj 4 , Christoph Mayer 4 , Filipp Oesterhelt 2 , Sofia Friães 1 , Beatriz Royo 1 , Tanja Schneider 3 , Heike Brötz-Oesterhelt 2 , Carlos C Romão 1 , Lígia M Saraiva 1
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Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)3(2,2′-bipyridyl)(azole)]+ display important synergies against several microbes. We carried out a structure–activity relationship study based upon the lead structure of [Mn(CO)3(Bpy)(Ctz)]+ by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO)3(Bpy)(Ctz)]+ is more than the sum of its parts: while precursor [Re(CO)3(Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO)3(Bpy)(Ctz)]+ is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO)3(Bpy)(Ctz)]+ to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate’s activity relative to that of the antibiotic alone.
中文翻译：
克霉唑连接的CO释放分子的协同抗菌活性和机制
几种金属基一氧化碳释放分子 (CORM) 是活性 CO 供体，具有确定的抗菌活性。其中，CORM 与 [Mn(CO) 3 (2,2'-联吡啶基)(唑)] +型唑类抗生素的偶联物对多种微生物具有重要的协同作用。我们基于[Mn(CO) 3 (Bpy)(Ctz)] +的铅结构进行了构效关系研究通过生产具有不同金属和配体的克霉唑 (Ctz) 缀合物。我们得出结论，二齿配体的性质强烈影响杀菌活性，用小的双环配体取代联吡啶基导致高活性克霉唑缀合物。相反，金属不影响活性。我们发现共轭物 [Re(CO) 3 (Bpy)(Ctz)] +大于其部分的总和：而前体 [Re(CO) 3 (Bpy)Br] 没有抗菌活性，克霉唑仅显示中等抑制浓度，[Re(CO) 3 (Bpy)(Ctz)]的效力+比克霉唑高一个数量级，细菌目标菌种的谱包括革兰氏阳性菌和革兰氏阴性菌。[Re(CO) 3 (Bpy)(Ctz)] +加入金黄色葡萄球菌对膜拓扑结构产生普遍影响，对肽聚糖生物合成具有抑制作用，并影响能量功能。这种 CORM 偶联物的作用机制涉及一系列由膜插入引发的事件，随后是膜解体、肽聚糖合成抑制、CO 释放和膜电位破坏。这些结果表明，CORM 与已知抗生素的缀合可能会产生具有协同效应的有用结构，与单独的抗生素相比，这些结构会增加缀合物的活性。
更新日期：2022-04-08
中文翻译：
克霉唑连接的CO释放分子的协同抗菌活性和机制
几种金属基一氧化碳释放分子 (CORM) 是活性 CO 供体，具有确定的抗菌活性。其中，CORM 与 [Mn(CO) 3 (2,2'-联吡啶基)(唑)] +型唑类抗生素的偶联物对多种微生物具有重要的协同作用。我们基于[Mn(CO) 3 (Bpy)(Ctz)] +的铅结构进行了构效关系研究通过生产具有不同金属和配体的克霉唑 (Ctz) 缀合物。我们得出结论，二齿配体的性质强烈影响杀菌活性，用小的双环配体取代联吡啶基导致高活性克霉唑缀合物。相反，金属不影响活性。我们发现共轭物 [Re(CO) 3 (Bpy)(Ctz)] +大于其部分的总和：而前体 [Re(CO) 3 (Bpy)Br] 没有抗菌活性，克霉唑仅显示中等抑制浓度，[Re(CO) 3 (Bpy)(Ctz)]的效力+比克霉唑高一个数量级，细菌目标菌种的谱包括革兰氏阳性菌和革兰氏阴性菌。[Re(CO) 3 (Bpy)(Ctz)] +加入金黄色葡萄球菌对膜拓扑结构产生普遍影响，对肽聚糖生物合成具有抑制作用，并影响能量功能。这种 CORM 偶联物的作用机制涉及一系列由膜插入引发的事件，随后是膜解体、肽聚糖合成抑制、CO 释放和膜电位破坏。这些结果表明，CORM 与已知抗生素的缀合可能会产生具有协同效应的有用结构，与单独的抗生素相比，这些结构会增加缀合物的活性。
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