Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, United States.
Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States.
Front Cell Infect Microbiol. 2023 Jan 6;12:1085946. doi: 10.3389/fcimb.2022.1085946. eCollection 2022.
Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.
联合治疗对于治疗结核病是必要的，以降低疾病复发率和防止耐药性的产生，并且迫切需要更短的治疗方案。分枝杆菌适应感染中的各种病变微环境会诱导不同状态的缓慢复制和不复制，以及随后的抗生素耐受。这种非遗传性的治疗耐受需要长时间的联合治疗。因此，开发针对感染中不同类型的耐药细胞的联合治疗方法至关重要。随着新的工具被积极开发以在药物开发管道的早期研究药物组合，我们必须考虑如何最好地模拟耐药细胞，以利用这些工具设计针对这些细胞的最佳抗生素组合，从而缩短结核病的治疗时间。在这篇综述中，我们讨论了耐药性的不同类型的基础因素，联合治疗如何针对这些细菌群体，以及目前如何对耐多药结核病的发展进行耐药性建模。我们强调了未来研究的领域，以开发更好地模拟结核病感染中的耐药性的新工具，特别是用于联合治疗测试，以便将最佳的药物方案推向临床。
