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.
Bibliographical noteFunding Information:
We thank Dr Juan Guerrero for advice and assistance in 1H NMR analysis. E.H.M. is supported by grant ‘Fondecyt Postdoctorado 3150004’, CONICYT, Chile. J.P.S. is supported by National Institutes of Health Grants 1R01HG005084. C.L.M. and J.N. are supported by National Institutes of Health Grants 1R01HG005084, 1R01GM104975 and R01HG005853 and National Science Foundation Grant DBI 0953881. S.W.S. is supported by an NSF Graduate Research Fellowship (00039202), an NIH Biotechnology training grant (T32GM008347). F.A.A. is supported by grant ‘Fondecyt de Iniciación en la Investigación 11140334’, CONICYT, Chile. H.M. is supported by grants JSPS Kakenhi 25250028, 16H02485 and MEXT Kakenhi 25108716, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. C.C.V. is supported by grants ‘Fondecyt Regular 1130362 and 1160051’, CONICYT, Chile.
© The Author(s) 2017.