Ackart David F, Lindsey Erick A, Podell Brendan K, Melander Roberta J, Basaraba Randall J, Melander Christian
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Pathog Dis. 2014 Apr;70(3):370-8. doi: 10.1111/2049-632X.12143. Epub 2014 Feb 24.
The expression of phenotypic drug resistance or drug tolerance serves as a strategy for Mycobacterium tuberculosis to survive in vivo antimicrobial drug treatment; however, the mechanisms are poorly understood. Progress toward a more in depth understanding of in vivo drug tolerance and the discovery of new therapeutic strategies designed specifically to treat drug-tolerant M. tuberculosis are hampered by the lack of appropriate in vitro assays. A library of 2-aminoimidazole-based small molecules combined with the antituberculosis drug isoniazid was screened against M. tuberculosis expressing in vitro drug tolerance as microbial communities attached to an extracellular matrix derived from lysed leukocytes. Based on the ability of nine of ten 2-aminoimidazole compounds to inhibit Mycobacterium smegmatis biofilm formation and three of ten molecules capable of dispersing established biofilms, two active candidates and one inactive control were tested against drug-tolerant M. tuberculosis. The two active compounds restored isoniazid susceptibility as well as reduced the in vitro minimum inhibitory concentrations of isoniazid in a dose-dependent manner. The dispersion of drug-tolerant M. tuberculosis with 2-aminoimidazole-based small molecules as an adjunct to antimicrobial treatment has the potential to be an effective antituberculosis treatment strategy designed specifically to eradicate drug-tolerant M. tuberculosis.
表型耐药或药物耐受性的表达是结核分枝杆菌在体内抗菌药物治疗中存活的一种策略；然而，其机制尚不清楚。由于缺乏合适的体外检测方法，对体内药物耐受性的更深入理解以及专门用于治疗耐多药结核分枝杆菌的新治疗策略的发现受到了阻碍。针对附着于裂解白细胞来源的细胞外基质上的微生物群落，对表达体外药物耐受性的结核分枝杆菌进行了基于2-氨基咪唑的小分子文库与抗结核药物异烟肼的联合筛选。基于十种2-氨基咪唑化合物中有九种能够抑制耻垢分枝杆菌生物膜形成，以及十种分子中有三种能够分散已形成的生物膜的能力，对两种活性候选物和一种非活性对照物进行了耐多药结核分枝杆菌测试。这两种活性化合物恢复了异烟肼的敏感性，并以剂量依赖的方式降低了异烟肼的体外最低抑菌浓度。以基于2-氨基咪唑的小分子作为抗菌治疗的辅助手段来分散耐多药结核分枝杆菌，有可能成为一种专门设计用于根除耐多药结核分枝杆菌的有效抗结核治疗策略。
