Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile.
University of Minnesota-Twin Cities, Bioinformatics and Computational Biology, Minneapolis, Minnesota 55455, USA.
Nat Commun. 2017 May 11;8:15320. doi: 10.1038/ncomms15320.
The metalloid tellurite is highly toxic to microorganisms. Several mechanisms of action have been proposed, including thiol depletion and generation of hydrogen peroxide and superoxide, but none of them can fully explain its toxicity. Here we use a combination of directed evolution and chemical and biochemical approaches to demonstrate that tellurite inhibits heme biosynthesis, leading to the accumulation of intermediates of this pathway and hydroxyl radical. Unexpectedly, the development of tellurite resistance is accompanied by increased susceptibility to hydrogen peroxide. Furthermore, we show that the heme precursor 5-aminolevulinic acid, which is used as an antimicrobial agent in photodynamic therapy, potentiates tellurite toxicity. Our results define a mechanism of tellurite toxicity and warrant further research on the potential use of the combination of tellurite and 5-aminolevulinic acid in antimicrobial therapy.
碲酸盐是一种对微生物具有高度毒性的类金属。已经提出了几种作用机制，包括巯基耗竭和过氧化氢和超氧化物的产生，但没有一种机制可以完全解释其毒性。在这里，我们使用定向进化和化学及生化方法的组合来证明碲酸盐抑制血红素生物合成，导致该途径的中间体和羟基自由基的积累。出乎意料的是，碲酸盐抗性的发展伴随着对过氧化氢敏感性的增加。此外，我们表明，血红素前体 5-氨基酮戊酸，它被用作光动力疗法中的抗菌剂，增强了碲酸盐的毒性。我们的结果定义了碲酸盐毒性的机制，并证明了在抗菌治疗中联合使用碲酸盐和 5-氨基酮戊酸的潜在用途的进一步研究是合理的。
