Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.
Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.
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DOI：
10.1371/journal.ppat.1006974
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发表时间：
2018-04
期刊：
影响因子：
6.7
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Xu Y;Wang L;Zimmerman MD;Chen KY;Huang L;Fu DJ;Kaya F;Rakhilin N;Nazarova EV;Bu P;Dartois V;Russell DG;Shen X
结核分枝杆菌（Mtb）不断出现耐药菌株，仍然对世界健康构成严重威胁。结核分枝杆菌感染的一个显着特征是感染部位宿主组织的广泛重编程。在这里，我们报告通过一组小分子抑制剂抑制基质金属蛋白酶（MMP）活性，增强一线结核病药物异烟肼（INH）和利福平（RIF）的体内效力。抑制 MMP 活性会导致周细胞覆盖的血管数量增加，并且似乎可以稳定受感染肺组织的完整性。在接受治疗的小鼠中，我们观察到一线结核病药物在受感染肺部的输送和/或保留增加，从而增强了药物疗效。这些发现表明，针对 Mtb 诱导的宿主组织重塑可以提高治疗效果，并可以增强当前药物治疗方案的有效性。结核分枝杆菌 (Mtb) 仍然是全球单一传染源导致死亡的主要原因，2015 年导致 180 万人死亡。所需的长期治疗（6-9 个月）及其所有现有问题，可能会促进耐多药 (MDR) 结核菌株的出现，因此迫切需要缩短治疗时间的策略。 Mtb 作为病原体的成功取决于其重塑宿主组织的能力，其特征是细胞外基质 (ECM) 沉积和渗漏血管化。在这里，我们报告说，抑制基质金属蛋白酶（MMP）可显着增强一线结核病抗生素的效力。这些 MMP 抑制剂增加了感染部位健康血管与渗漏功能障碍血管的相对比例，并增强了药物输送和/或保留。我们的研究强调了针对 Mtb 诱导的宿主组织重塑以增强当前一线抗生素功效的潜力。它还提出了一种替代治疗策略来修复结核肉芽肿中的渗漏血管，以增强药物输送。 MMP 抑制剂的重新利用可能是缩短结核病治疗时间和对抗耐多药菌株出现的关键。
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. Mycobacterium tuberculosis (Mtb) continues to be the leading cause of death from a single infectious agent worldwide, leading to 1.8 million deaths in 2015. The long treatment required (6–9 months), with all of its incumbent problems, can promote the emergence of multidrug-resistant (MDR) TB strains, so strategies to shorten the treatment duration are in dire need. Mtb’s success as a pathogen hinges on its ability to remodel the host tissue, characterized by extracellular matrix (ECM) deposition and leaky vascularization. Here we report that inhibition of matrix metalloproteinases (MMPs) significantly enhances the potency of frontline TB antibiotics. These MMP inhibitors increase the relative proportion of healthy blood vessels versus leaky dysfunctional vessels at the infection site, and enhance drug delivery and/or retention. Our study highlights the potential of targeting Mtb-induced host tissue remodeling to enhance the efficacy of current frontline antibiotics. It also suggests an alternative therapeutic strategy to repair the leaky blood vessels in TB granulomas to enhance drug delivery. Repurposing of MMP inhibitors may hold the key to shortening TB treatments and combating the emergence of MDR strains.
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影响因子：
4.6
作者：
Egawa, Gyohei;Nakamizo, Satoshi;Natsuaki, Yohei;Doi, Hiromi;Miyachi, Yoshiki;Kabashima, Kenji
通讯作者：
Kabashima, Kenji
影响因子：
3.2
作者：
Izzo, AA;Izzo, LS;Majka, S
通讯作者：
Majka, S
DOI：
10.1046/j.1365-2613.2000.00152.x
发表时间：
2000-06-01
影响因子：
3
作者：
Hernandez-Pando, R;Orozco, H;Rook, G
通讯作者：
Rook, G
影响因子：
45.3
作者：
Giantonio, Bruce J.;Catalano, Paul J.;Benson, Al B., III
通讯作者：
Benson, Al B., III
影响因子：
15.9
作者：
Elkington, Paul;Shiomi, Takayuki;Friedland, Jon S.
通讯作者：
Friedland, Jon S.