PDF(Pubmed)
Abstract：
Mycobacterium abscessus infections are emerging in cystic fibrosis patients, and treatment success rate in these patients is only 33% due to extreme antibiotic resistance. Thus, new treatment options are essential. An interesting target could be Lsr2, a nucleoid-associated protein involved in mycobacterial virulence. Zafirlukast is a Food and Drug Administration (FDA)-approved drug against asthma that was shown to bind Lsr2. In this study, zafirlukast treatment is shown to reduce M. abscessus growth, with a minimal inhibitory concentration of 16 µM and a bactericidal concentration of 64 µM in replicating bacteria only. As an initial response, DNA condensation, a known stress response of mycobacteria, occurs after 1 h of treatment with zafirlukast. During continued zafirlukast treatment, the morphology of the bacteria alters and the structural integrity of the bacteria is lost. After 4 days of treatment, reduced viability is measured in different culture media, and growth of M. abscessus is reduced in a dose-dependent manner. Using transmission electron microscopy, we demonstrated that the hydrophobic multilayered cell wall and periplasm are disorganized and ribosomes are reduced in size and relocalized. In summary, our data demonstrate that zafirlukast alters the morphology of M. abscessus and is bactericidal at 64 µM. The bactericidal concentration of zafirlukast is relatively high, and it is only effective on replicating bacteria but as zafirlukast is an FDA-approved drug, and currently used as an anti-asthma treatment, it could be an interesting drug to further study in in vivo experiments to determine whether it could be used as an antibiotic for M. abscessus infections.
摘要：
囊性纤维化患者出现脓肿分枝杆菌感染，由于极端的抗生素耐药性，这些患者的治疗成功率仅为33%。因此，新的治疗方案至关重要。一个有趣的靶标可能是Lsr2，一种与分枝杆菌毒力有关的类核相关蛋白。扎鲁司特是食品和药物管理局（FDA）批准的抗哮喘药物，已显示可结合Lsr2。在这项研究中,扎鲁司特治疗可减少脓肿分枝杆菌的生长，仅在复制细菌中具有16µM的最小抑制浓度和64µM的杀菌浓度。作为最初的回应，DNA缩合,已知的分枝杆菌应激反应，发生在扎鲁司特治疗1小时后。在继续扎鲁司特治疗期间，细菌的形态改变并且细菌的结构完整性丧失。治疗4天后，在不同的培养基中测量降低的活力，脓肿分枝杆菌的生长以剂量依赖性方式减少。使用透射电子显微镜，我们证明了疏水性多层细胞壁和周质杂乱无章，核糖体大小减小并重新定位。总之,我们的数据表明，扎鲁司特改变了脓肿分枝杆菌的形态，并且在64µM时具有杀菌性。扎鲁司特的杀菌浓度相对较高，它仅对复制细菌有效，但由于扎鲁司特是FDA批准的药物，目前用作抗哮喘治疗，它可能是一种有趣的药物，可以在体内实验中进一步研究，以确定它是否可以用作脓肿分枝杆菌感染的抗生素。
