Comparative Studies to Uncover Mechanisms of Action of N-(1,3,4-Oxadiazol-2-yl)benzamide Containing Antibacterial Agents.
Comparative Studies to Uncover Mechanisms of Action of N-(1,3,4-Oxadiazol-2-yl)benzamide Containing Antibacterial Agents.
复制标题
DOI：
10.1021/acsinfecdis.1c00613
复制
发表时间：
2022-04-08
影响因子：
5.3
通讯作者：
Sintim, Herman O.
中科院分区：
文献类型：
--
作者：
Naclerio, George A.;Onyedibe, Kenneth, I;Karanja, Caroline W.;Aryal, Uma K.;Sintim, Herman O.
尽管有许多抗生素可用，耐药细菌病原体每年仍造成高死亡率。耐甲氧西林金黄色葡萄球菌（MRSA）的问题尤其严重，对万古霉素和利奈唑胺等一线治疗药物的耐药性上升，需要新的化学方法来治疗慢性和复发性MRSA感染。卤代N-（1,3,4-恶二唑-2-基）苯酰胺是一类有趣的抗菌药物，已被多个研究小组描述为对不同的细菌病原体有效。几种N-（1,3,4-恶二唑-2-基）苯酰胺的作用方式已被阐明。例如，恶二唑KKL-35和MBX-4132被描述为反翻译（核糖体拯救途径）的抑制剂，而HSGN-94被证明可以抑制脂磷胆酸。然而，其他类似的卤化N-（1,3,4-恶二唑-2-基）苯酰胺既不抑制反式翻译也不抑制脂磷胆酸的生物合成，但却是有效的抗菌剂。例如，HSGN-220、- 218和- 144是用OCF3、SCF3或SF5修饰的N-（1,3,4-恶二唑-2-基）苯酰胺，对MRSA临床分离株具有显著的最低抑制浓度（mic），范围为1 μg/mL至0.06 μg/mL，并且在30天内对MRSA表现出较低的耐药倾向。然而，这些高效的恶二唑的作用机制尚不清楚。为了深入了解这些卤化N-(1,3,4-oxadiazol-2-yl)苯酰胺如何抑制细菌生长，我们对HSGN-220、- 218和- 144处理过的金黄色葡萄球菌的一些必需基因进行了全球蛋白质组学和RNA表达分析。这些研究表明，恶二唑HSGN-220、- 218和- 144是多靶点抗生素，可调节甲基萘醌生物合成和其他必需蛋白如DnaX、Pol IIIC、BirA、LexA和DnaC。此外，这些卤化的N-（1,3,4-恶二唑-2-基）苯酰胺能够使细菌膜去极化，并调节铁载体的生物合成和血红素的调节。铁饥饿似乎是导致细菌死亡的作用机制的一部分。本研究表明，N-（1,3,4-恶二唑-2-基）苯酰胺确实是开发抗菌剂的优越支架，并且细微的修饰会导致作用机制的改变。
Drug-resistant bacterial pathogens still cause high levels mortality annually despite the availability of many antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) is especially problematic and the rise in resistance to front line treatments like vancomycin and linezolid calls for new chemical modalities to treat chronic and relapsing MRSA infections. Halogenated N-(1,3,4-oxadiazol-2-yl)benzamides are interesting class of antimicrobial agents, which have been described by multiple groups to be effective against different bacterial pathogens. The modes of action of a few N-(1,3,4-oxadiazol-2-yl)benzamides have been elucidated. For example, oxadiazoles KKL-35 and MBX-4132, have been described as inhibitors of trans-translation (a ribosome rescue pathway) while HSGN-94 was shown to inhibit lipoteichoic acid. However other similarly halogenated N-(1,3,4-oxadiazol-2-yl)benzamides neither inhibit trans-translation nor lipoteichoic acid biosynthesis but are potent antimicrobial agents. For example, HSGN-220, −218, and −144 are N-(1,3,4-oxadiazol-2-yl)benzamides that are modified with OCF3, SCF3 or SF5, and have remarkable minimum inhibitory concentrations (MICs) ranging from 1 μg/mL to 0.06 μg/mL against MRSA clinical isolates and show a low propensity to resistance to MRSA over 30 days. The mechanism of action of these highly potent oxadiazoles is however unknown. To provide insights into how these halogenated N-(1,3,4-oxadiazol-2-yl)benzamides inhibit bacterial growth, we performed global proteomics and RNA expression analysis of some essential genes of S. aureus treated with HSGN-220, −218, and −144. These studies revealed that the oxadiazoles HSGN-220, −218, and −144 are multi-targeting antibiotics that regulate menaquinone biosynthesis and other essential proteins like DnaX, Pol IIIC, BirA, LexA, and DnaC. In addition, these halogenated N-(1,3,4-oxadiazol-2-yl)benzamides were able to depolarize bacterial membranes and regulate siderophore biosynthesis and heme regulation. Iron starvation appears to be part of the mechanism of action that led to bacterial killing. This study demonstrates that N-(1,3,4-oxadiazol-2-yl)benzamides are indeed privileged scaffolds for the development of antibacterial agents and that subtle modifications lead to changes to mechanism of action.
登录
查看更多内容
影响因子：
4.4
作者：
Chaudhuri RR;Allen AG;Owen PJ;Shalom G;Stone K;Harrison M;Burgis TA;Lockyer M;Garcia-Lara J;Foster SJ;Pleasance SJ;Peters SE;Maskell DJ;Charles IG
通讯作者：
Charles IG
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
3.9
作者：
Boersch, M.;Rudrawar, S.;Grant, G.;Zunk, M.
通讯作者：
Zunk, M.
影响因子：
15.8
作者：
de Kraker ME;Stewardson AJ;Harbarth S
通讯作者：
Harbarth S
影响因子：
10.5
作者：
Hammer ND;Skaar EP
通讯作者：
Skaar EP