Complex effects of macrolide venturicidins on bacterial F-ATPases likely contribute to their action as antibiotic adjuvants.
Complex effects of macrolide venturicidins on bacterial F-ATPases likely contribute to their action as antibiotic adjuvants.
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DOI：
10.1038/s41598-021-93098-8
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发表时间：
2021-07-01
影响因子：
4.6
通讯作者：
Duncan TM
中科院分区：
文献类型：
--
作者：
Milgrom YM;Duncan TM
细菌能量代谢现在被认为是抗生素功效的关键因素。 F 型 ATP 酶/ATP 合酶 (FOF1) 是细菌和真核生物细胞生物能学的核心参与者，贝达喹啉在对抗多重耐药结核病方面的成功证实了其作为选择性抗生素靶标的潜力。文丘里菌素大环内酯类化合物最初因其抗真菌特性而被鉴定，并被发现能特异性抑制真核生物和细菌的 FOF1。文丘里菌素本身并不是有效的抗菌剂，但最近发现其具有佐剂活性，增强了氨基糖苷类抗生素对抗多种耐药细菌的功效。在这里，我们发现文丘里杀素对大肠杆菌和铜绿假单胞菌细菌膜中 FOF1 的 ATP 酶活性有更复杂的影响。我们的主要发现是，较高浓度的文丘里菌素会诱导 F1-ATP 酶活性与受文丘里菌素抑制的质子传输 FO 复合物发生时间和 ATP 依赖性解偶联。在之前的铜绿假单胞菌和金黄色葡萄球菌研究中，这种失调的 ATP 酶活性可能是文丘里杀素诱导的细胞 ATP 消耗的关键因素。对这种功能解偶联如何发生的进一步研究可以指导针对 F 型 ATP 酶/ATP 合酶的新型抗生素和/或佐剂的开发。
Bacterial energy metabolism is now recognized as a critical factor for the efficacy of antibiotics. The F-type ATPase/ATP synthase (FOF1) is a central player in cellular bioenergetics of bacteria and eukaryotes, and its potential as a selective antibiotic target has been confirmed by the success of bedaquiline in combatting multidrug-resistant tuberculosis. Venturicidin macrolides were initially identified for their antifungal properties and were found to specifically inhibit FOF1 of eukaryotes and bacteria. Venturicidins alone are not effective antibacterials but recently were found to have adjuvant activity, potentiating the efficacy of aminoglycoside antibiotics against several species of resistant bacteria. Here we discovered more complex effects of venturicidins on the ATPase activity of FOF1 in bacterial membranes from Escherichia coli and Pseudomonas aeruginosa. Our major finding is that higher concentrations of venturicidin induce time– and ATP–dependent decoupling of F1-ATPase activity from the venturicidin-inhibited, proton-transporting FO complex. This dysregulated ATPase activity is likely to be a key factor in the depletion of cellular ATP induced by venturicidins in prior studies with P. aeruginosa and Staphylococcus aureus. Further studies of how this functional decoupling occurs could guide development of new antibiotics and/or adjuvants that target the F-type ATPase/ATP synthase.
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影响因子：
16.6
作者：
Koul, Anil;Vranckx, Luc;Dhar, Neeraj;Gohlmann, Hinrich W. H.;Oezdemir, Emre;Neefs, Jean-Marc;Schulz, Melanie;Lu, Ping;Mortz, Ejvind;McKinney, John D.;Andries, Koen;Bald, Dirk
通讯作者：
Bald, Dirk
影响因子：
64.8
作者：
Guo, Hui;Courbon, Gautier M.;Rubinstein, John L.
通讯作者：
Rubinstein, John L.
DOI：
10.1073/pnas.1523199113
发表时间：
2016-06-28
影响因子：
11.1
作者：
Bosi, Emanuele;Monk, Jonathan M.;Palsson, Bernhard O.
通讯作者：
Palsson, Bernhard O.
影响因子：
3.6
作者：
Glasser NR;Kern SE;Newman DK
通讯作者：
Newman DK
影响因子：
6.7
作者：
Grosser MR;Paluscio E;Thurlow LR;Dillon MM;Cooper VS;Kawula TH;Richardson AR
通讯作者：
Richardson AR