The Robert H. Smith faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
Microbiol Spectr. 2022 Dec 21;10(6):e0262322. doi: 10.1128/spectrum.02623-22. Epub 2022 Nov 2.
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 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 gene (), 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 gene cluster across several mycobacteria. The Tn_ 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_ mutant during iron deprivation. The transcriptomic response of the Tn 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 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 ) may differ between M. abscessus and Mtb. 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 gene required for the biosynthesis of siderophore mycobactin in M. abscessus. We show that the gene s required for growth during iron deprivation and can be compensated by several supplements, including, surprisingly, albumin. We also show the transcriptomic response of the -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.
脓肿分枝杆菌是一种新兴的病原体，其生长和发病机制严重依赖铁。分枝杆菌属通过称为分枝菌酸的铁载体来获取铁，这些铁载体由基因簇合成，但该基因簇在适应铁限制方面的作用尚未确定。我们鉴定了一个脓肿分枝杆菌 Tn_突变体，该突变体中断了基因（），这是分枝菌酸生物合成的核心组成部分。我们比较了野生型（WT）细菌在铁限制条件下的生长特性、对补充物的依赖性和转录组反应，以此来测试该分离株。我们还比较了几种分枝杆菌中基因簇的结构。Tn_突变体的生长缺陷明显，但不是绝对的，在铁限制培养基中更为明显。用分枝菌酸 J、血红素、血液和令人惊讶的白蛋白补充可挽救生长不良。同样，WT 细菌分泌的成熟（羧基）-分枝菌酸也可在缺铁时挽救 Tn_突变体。Tn_突变体的转录组反应涉及到已知与铁稳态相关的基因的上调，与在铁限制条件下生长的 WT 细菌的反应相当。有趣的是，该反应与结核分枝杆菌对铁限制的反应并不完全相同。基因簇和分枝菌酸在脓肿分枝杆菌的生理中发挥重要作用。（羧基）-分枝菌酸从 WT 细菌中分泌出来，可以作为“公共利益”。几种铁稳态相关基因（如）在脓肿分枝杆菌和 Mtb 之间的作用可能不同。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，在身体虚弱的个体中可引起严重的肺部疾病。目前人们对该细菌如何获取铁还知之甚少。在这里，我们首次对脓肿分枝杆菌中合成铁载体分枝菌酸所需的基因的作用进行了描述。我们表明，基因在缺铁时的生长是必需的，并且可以通过几种补充物来补偿，包括令人惊讶的白蛋白。我们还表明，-突变体的转录组反应与亲本菌株对铁饥饿的反应相当，并且似乎与结核分枝杆菌的反应不同。这些结果表明，在脓肿分枝杆菌和 NTM 菌株中研究分枝菌酸是很重要的。了解该途径对于理解宿主内铁的获取及其在发病机制中的作用至关重要，这反过来可能有助于开发抗分枝杆菌治疗药物。
