A Pivotal Role for Mycobactin/mbtE in Growth and Adaptation of Mycobacterium abscessus.
A Pivotal Role for Mycobactin/mbtE in Growth and Adaptation of Mycobacterium abscessus.
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DOI：
10.1128/spectrum.02623-22
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发表时间：
2022-12-21
影响因子：
3.7
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中科院分区：
文献类型：
--
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脓肿分枝杆菌是一种新兴的病原体，严重依赖铁的生长和发病。结核分枝杆菌的铁获取是由称为分枝杆菌素的铁载体控制的，由mbt基因簇合成，但该基因簇在脓肿分枝杆菌适应铁限制中的作用尚未确定。我们发现了一个脓肿分枝杆菌tn_突变体，其mbtE基因（mab2248c）中断，这是分枝杆菌素生物合成的核心成分。我们测试了该分离菌的生长特性、对补充剂的依赖性和转录组反应，并将其与野生型（WT）细菌在限铁条件下的反应进行了比较。我们还比较了几种分枝杆菌的mbt基因簇的结构。Tn_mbtE突变体有明显的生长缺陷，但不是绝对的，这种缺陷在限铁培养基中更为明显。补充分枝杆菌素- j、血红蛋白、血液和令人惊讶的白蛋白，挽救了不良的生长。同样，WT细菌分泌的成熟（羧基）分枝杆菌素在缺铁过程中拯救了Tn_mbtE突变体。Tn_mbtE突变体的转录组反应涉及已知与铁稳态有关的基因的上调，与在限铁条件下生长的WT细菌的转录组反应相当。有趣的是，这种反应与结核分枝杆菌对铁限制的反应不同。mbt基因簇和分枝杆菌素在脓疡分枝杆菌的生理中起重要作用。（羧基）-mycobactin是由WT细菌分泌的，可以作为“公共物品”。一些铁稳态相关基因（如ideR）的作用可能在脓肿分枝杆菌和结核分枝杆菌之间有所不同。重要性：脓肿分枝杆菌是一种新兴的人类病原体，属于非结核分枝杆菌（NTM）家族，在感染个体中引起严重的肺部疾病。人们对这种细菌如何获取铁知之甚少。在这里，我们提供了第一个表征mbtE基因在脓肿分枝杆菌中铁载体菌素生物合成所需的作用。我们发现mbtE基因是缺铁期间生长所必需的，并且可以通过几种补充剂来补偿，令人惊讶的是，其中包括白蛋白。我们还表明，mbte突变体的转录组反应与亲本菌株对铁饥饿的反应相当，似乎与结核分枝杆菌的反应不同。这些结果表明研究脓肿分枝杆菌和NTM菌株中的分枝杆菌素具有重要意义。了解这一途径对于理解宿主体内铁的获取及其在发病机制中的作用至关重要，这反过来又可能促进抗真菌治疗的发展。
Mycobacterium abscessus is an emerging pathogen that critically depends on iron for growth and pathogenesis. The acquisition of iron in Mycobacterium tuberculosis is governed by siderophores called mycobactins, synthesized by the mbt gene cluster, but the role of this gene cluster in the adaption of M. abscessus to iron limitation is not characterized. We identified an M. abscessus Tn_mutant with interruption of the mbtE gene (MAB_2248c), a central component of mycobactin biosynthesis. We tested this isolate growth characteristic, dependency on supplements, and transcriptomic response, comparing it to the response of wild-type (WT) bacteria in iron-limiting conditions. We also compare the structure of the mbt gene cluster across several mycobacteria. The Tn_mbtE mutant had a substantial, but not absolute, growth defect, which was more substantial in iron-limited media. Supplementation with mycobactin-J, hemin, blood, and surprisingly, albumin, salvaged the poor growth. Similarly, secreted mature (carboxy)-mycobactins from WT bacteria rescued the Tn_mbtE mutant during iron deprivation. The transcriptomic response of the Tn_mbtE mutant involved the upregulation of genes known to be implicated in iron homeostasis and was comparable to that of WT bacteria grown in iron-limiting conditions. Interestingly, the response was not identical to the response of M. tuberculosis to iron limitation. The mbt gene cluster and mycobactins play important roles in the physiology of M. abscessus. (Carboxy)-mycobactin is secreted from WT bacteria and can serve as “public good.” The role of several iron-homeostasis related genes (like ideR) may differ between M. abscessus and Mtb. IMPORTANCE Mycobacterium abscessus is an emerging human pathogen belonging to the nontuberculous mycobacteria (NTM) family, causing severe pulmonary disease in compromised individuals. How this bacterium acquires iron is poorly understood. Here, we provide the first characterization of the role(s) the mbtE gene required for the biosynthesis of siderophore mycobactin in M. abscessus. We show that the gene mbtE is required for growth during iron deprivation and can be compensated by several supplements, including, surprisingly, albumin. We also show the transcriptomic response of the mbtE-mutant is comparable to the response of the parental strain to iron starvation and seems different from the response of M. tuberculosis. These results indicate the importance of studying mycobactin in M. abscessus and NTM strains. Understanding this pathway is central to understanding the acquisition of iron within hosts and its role in pathogenesis, which in turn may facilitate the development of antimycobacterial therapeutics.
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影响因子：
6.4
作者：
Foreman M;Gershoni M;Barkan D
通讯作者：
Barkan D
影响因子：
3.1
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.6
作者：
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