Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, United States of America.
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States of America.
PLoS Pathog. 2018 Apr 26;14(4):e1006974. doi: 10.1371/journal.ppat.1006974. eCollection 2018 Apr.
Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.
结核分枝杆菌（Mtb）仍然是世界卫生的严重威胁，新出现的耐药菌株更是如此。Mtb 感染的一个突出特点是感染部位宿主组织的广泛重编程。在这里，我们报告说，一组小分子抑制剂抑制基质金属蛋白酶（MMP）的活性，可增强一线抗结核药物异烟肼（INH）和利福平（RIF）的体内效力。抑制 MMP 活性可导致周细胞覆盖的血管数量增加，并且似乎稳定了受感染的肺组织的完整性。在治疗的小鼠中，我们观察到一线抗结核药物在感染肺部中的递送和/或保留增加，从而增强了药物疗效。这些发现表明，靶向 Mtb 诱导的宿主组织重塑可以提高治疗效果，并可能增强当前药物方案的有效性。
