Abstract
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.
Highlights
The metalloid tellurite is highly toxic to microorganisms
Individual colonies were tested for resistance following growth in lysogeny broth (LB) medium (Fig. 1b and Supplementary Fig. 1a) containing a μg ml–1 TeO32– 1.4
Our results indicate that the hemA mutation in strain EM2 shows a dominant effect on the increased tellurite resistance and suggests that altering the levels of aminolevulinic acid (ALA) and/or heme is required for this process
Summary
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. When expressed in E. coli, the products of the ars and tehAB operons do not increase tellurite efflux or alter its uptake[12], ruling out some potential resistance mechanisms. The current hypothesis of tellurite toxicity in bacteria is based on observations that tellurite depletes thiols[14], which alters the reduction potential of the cell[15], and elicits the production of reactive oxygen species (ROS) and ROS-detoxifying enzymes[16,17]. This hypothesis proposes that the main causes of tellurite toxicity is its oxidant nature[11]. Organisms that are ROS-resistant like Deinococcus radiodurans show only modest tellurite resistance[15]
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