Abstract：
OBJECTIVE: Extensively drug-resistant (XDR) Acinetobacter baumannii poses a severe threat to public health due to its ability to form biofilms and persister cells, which contributes to critical drug resistance and refractory device-associated infections. A novel strategy to alleviate such an emergency is to identify promising compounds that restore the antimicrobial susceptibility of existing antibiotics against refractory infections.
RESULTS: Here, we found a significant synergy among three combinations of SPR741, clarithromycin and erythromycin with a potent antimicrobial activity against XDR A. baumannii (SPR741/CLA/E at 8/10/10 μg ml-1 for XDR AB1069 and at 10/16/10 μg ml-1 for XDR AB1208, respectively). Moreover, the triple combination therapy exhibits a significant antipersister and antibiofilm effect against XDR strains. Mechanistic studies demonstrate that SPR741 may promote intracellular accumulation of macrolides by permeabilizing the outer membrane as well as disrupting membrane potential and further enhance the quorum sensing inhibition activity of the macrolides against XDR A. baumannii and its biofilms. In addition, the triple combination of SPR741 with clarithromycin and erythromycin was not easy to induce resistance in A. baumannii and had effective antimicrobial activity with low toxicity in vivo.
CONCLUSIONS: Collectively, these results reveal the potential of SPR741 in combination with clarithromycin and erythromycin as a clinical therapy for refractory infections caused by XDR A. baumannii.
RESULTS: Here, we found a significant synergy among three combinations of SPR741, clarithromycin and erythromycin with a potent antimicrobial activity against XDR A. baumannii (SPR741/CLA/E at 8/10/10 μg ml-1 for XDR AB1069 and at 10/16/10 μg ml-1 for XDR AB1208, respectively). Moreover, the triple combination therapy exhibits a significant antipersister and antibiofilm effect against XDR strains. Mechanistic studies demonstrate that SPR741 may promote intracellular accumulation of macrolides by permeabilizing the outer membrane as well as disrupting membrane potential and further enhance the quorum sensing inhibition activity of the macrolides against XDR A. baumannii and its biofilms. In addition, the triple combination of SPR741 with clarithromycin and erythromycin was not easy to induce resistance in A. baumannii and had effective antimicrobial activity with low toxicity in vivo.
CONCLUSIONS: Collectively, these results reveal the potential of SPR741 in combination with clarithromycin and erythromycin as a clinical therapy for refractory infections caused by XDR A. baumannii.
摘要：
目的：广泛耐药（XDR）鲍曼不动杆菌由于其形成生物膜和持久细胞的能力，对公众健康构成严重威胁，这有助于严重的耐药性和难治性设备相关感染。缓解这种紧急情况的新策略是鉴定有希望的化合物，这些化合物可以恢复现有抗生素对难治性感染的抗微生物敏感性。
结果：这里，我们发现SPR741,克拉霉素和红霉素的三种组合对XDR鲍曼不动杆菌具有有效的抗菌活性(SPR741/CLA/E对XDRAB1069为8/10/10μgml-1,对XDRAB1208为10/16/10μgml-1)具有显著的协同作用.此外，三联疗法对XDR菌株具有显着的抗凝和抗生物膜作用。机理研究表明，SPR741可以通过透化外膜以及破坏膜电位来促进大环内酯类药物的细胞内积累，并进一步增强大环内酯类药物对XDR鲍曼不动杆菌及其生物膜的群体感应抑制活性。此外,SPR741与克拉霉素和红霉素的三重组合不易引起鲍曼不动杆菌的耐药性，并且具有有效的抗菌活性，体内毒性低。
结论：总的来说，这些结果揭示了SPR741联合克拉霉素和红霉素作为临床治疗XDR鲍曼不动杆菌引起的难治性感染的潜力.
结果：这里，我们发现SPR741,克拉霉素和红霉素的三种组合对XDR鲍曼不动杆菌具有有效的抗菌活性(SPR741/CLA/E对XDRAB1069为8/10/10μgml-1,对XDRAB1208为10/16/10μgml-1)具有显著的协同作用.此外，三联疗法对XDR菌株具有显着的抗凝和抗生物膜作用。机理研究表明，SPR741可以通过透化外膜以及破坏膜电位来促进大环内酯类药物的细胞内积累，并进一步增强大环内酯类药物对XDR鲍曼不动杆菌及其生物膜的群体感应抑制活性。此外,SPR741与克拉霉素和红霉素的三重组合不易引起鲍曼不动杆菌的耐药性，并且具有有效的抗菌活性，体内毒性低。
结论：总的来说，这些结果揭示了SPR741联合克拉霉素和红霉素作为临床治疗XDR鲍曼不动杆菌引起的难治性感染的潜力.
