Bicyclomycin Activity against Multidrug-Resistant Gram-Negative Pathogens.
Bicyclomycin Activity against Multidrug-Resistant Gram-Negative Pathogens.
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DOI：
10.1128/spectrum.03790-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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抗菌素耐药性的日益普遍对人类健康构成严重威胁。最难治疗的细菌感染是由多重耐药（MDR）革兰氏阴性病原体引起的感染，因为几乎没有有效的治疗方案。解决这一问题的一种方法是找到提高应用有限的旧抗菌剂活性的方法。双环霉素，一种转录终止抑制剂，是其中蛋白质或RNA合成的额外抑制增加双环霉素介导的对革兰氏阴性细菌的致死性的实例。为了研究双环霉素治疗MDR细菌病原体的潜力，我们首先测量了双环霉素和其他广泛使用的抗菌药物对100多种多重耐药革兰氏阴性临床分离株的MIC。双环霉素对碳青霉烯类耐药肠杆菌科（CRE）和大肠埃希菌的覆盖率良好（两种细菌的MIC 50/MIC 90均为25/50 μg/mL），对肺炎克雷伯菌的活性中等（MIC 50/MIC 90为50/200 μg/mL）。双环霉素也表现出协同作用（例如，分数抑制浓度[FIC]指数<0.5）与多西环素通过棋盘测定抑制细菌生长。虽然双环霉素本身对K.肺炎：该组合杀死的细菌比单独使用任何一种药物多100至1,000倍。在感染的鼠模型中，双环霉素-多西环素组合显示出比任一单独药剂更好的功效，并且组合治疗在很大程度上消除了由感染引起的组织病理学表现。因此，双环霉素，这在很大程度上是有限的治疗革兰氏阴性消化道感染，现在可以考虑联合治疗由CRE，E. coli和K.肺炎。重要性随着抗生素耐药性的持续增加，有效治疗多重耐药（MDR）革兰氏阴性菌感染的选择正在减少。寻找提高具有独特分子靶点的旧药剂的致命性的方法很重要，因为开发新的抗菌剂变得越来越困难。目前的工作表明，旧抗生素双环霉素对医院感染中经常遇到的三种重要类型的MDR革兰氏阴性病原体的多种临床分离株具有良好的抑菌活性，这是考虑扩大适应症所需的。更重要的是通过额外存在多西环素的协同生长抑制作用和杀伤增强，因为这增加了体内功效。这些数据表明，含双环霉素的方案有可能作为MDR革兰氏阴性菌感染的新治疗选择，如由CRE，E。coli和K.肺炎。
The growing prevalence of antimicrobial resistance poses a grave threat to human health. Among the most difficult bacterial infections to treat are those caused by multidrug-resistant (MDR) Gram-negative pathogens because few effective regimens are available. One approach to this problem is to find ways to increase the activity of old antimicrobials that had seen limited application. Bicyclomycin, an inhibitor of transcription termination, is an example in which the additional inhibition of protein or RNA synthesis increases bicyclomycin-mediated lethality against Gram-negative bacteria. To examine the potential of bicyclomycin for the treatment of MDR bacterial pathogens, we first measured the MICs of bicyclomycin and other widely used antimicrobials against more than 100 multidrug-resistant Gram-negative clinical isolates. Bicyclomycin showed good coverage of carbapenem-resistant Enterobacteriaceae (CRE) and Escherichia coli (MIC50/MIC90 of 25/50 μg/mL for both bacteria) and moderate activity against Klebsiella pneumoniae (MIC50/MIC90 of 50/200 μg/mL). Bicyclomycin also exhibited synergy (e.g., fractional inhibitory concentration [FIC] index of <0.5) with doxycycline for the inhibition of bacterial growth by a checkerboard assay. Although bicyclomycin exhibited very weak lethality by itself, it showed synthetic lethality with doxycycline against K. pneumoniae: the combination killed 100- to 1,000-fold more bacteria than either agent alone. In a murine model of infection, the bicyclomycin-doxycycline combination showed better efficacy than either agent alone, and the combination treatment largely eliminated histopathological manifestations caused by infection. Thus, bicyclomycin, which has largely been limited to the treatment of Gram-negative digestive tract infections, can now be considered for the combination treatment of systemic multidrug-resistant infections caused by CRE, E. coli, and K. pneumoniae. IMPORTANCE As antimicrobial resistance continues to increase, options for effectively treating multidrug-resistant (MDR) Gram-negative infections are declining. Finding ways to enhance the lethality of old agents that have unique molecular targets is important because developing new antimicrobials is becoming increasingly difficult. The present work showed that the old antibiotic bicyclomycin has good bacteriostatic activity against multiple clinical isolates of three significant types of MDR Gram-negative pathogens frequently encountered in hospital infections, as required for the consideration of expanded indications. More significant is the synergistic growth-inhibitory effect and the enhancement of killing by the additional presence of doxycycline since this increases the in vivo efficacy. These data demonstrate that bicyclomycin-containing regimens have potential as new treatment options for MDR Gram-negative infections such as those caused by CRE, E. coli, and K. pneumoniae.
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影响因子：
3.3
作者：
KAMIYA, T;MINE, Y;HASHIMOTO, M
通讯作者：
HASHIMOTO, M
影响因子：
5.2
作者：
Lee CR;Lee JH;Park KS;Kim YB;Jeong BC;Lee SH
通讯作者：
Lee SH
影响因子：
3.9
作者：
Beiras-Fernandez, Andres;Vogt, Ferdinand;Weis, Florian
通讯作者：
Weis, Florian
影响因子：
5.2
作者：
Malik, Muhammad;Li, Liping;Drlica, Karl
通讯作者：
Drlica, Karl
影响因子：
5.7
作者：
Skordalakes, E;Brogan, AR;Berger, JM
通讯作者：
Berger, JM