The proteobacterial species Burkholderia pseudomallei produces ergothioneine, which enhances virulence in mammalian infection

Abstract

Bacteria use various endogenous antioxidants for protection against oxidative stress associated with environmental survival or host infection. Although glutathione (GSH) is the most abundant and widely used antioxidant in Proteobacteria, ergothioneine (EGT) is another microbial antioxidant, mainly produced by fungi and Actinobacteria. The Burkholderia genus is found in diverse environmental niches. We observed that gene homologs required for the synthesis of EGT are widely distributed throughout the genus. By generating gene-deletion mutants and monitoring production with isotope-labeled substrates, we show that pathogenic Burkholderia pseudomallei and environmental B. thailandensis are able to synthesize EGT de novo. Unlike most other bacterial EGT synthesis pathways described, Burkholderia spp. use cysteine rather than γ-glutamyl cysteine as the thiol donor. Analysis of recombinant EgtB indicated that it is a proficient sulfoxide synthase, despite divergence in the active site architecture from that of mycobacteria. The absence of GSH, but not EGT, increased bacterial susceptibility to oxidative stresses in vitro. However, deletion of EGT synthesis conferred a reduced fitness to B. pseudomallei, with a delay in organ colonization and time to death during mouse infection. Therefore, despite the lack of an apparent antioxidant role in vitro, EGT is important for optimal bacterial pathogenesis in the mammalian host.-Gamage, A. M., Liao, C., Cheah, I. K., Chen, Y., Lim, D. R. X., Ku, J. W. K., Chee, R. S. L., Gengenbacher, M., Seebeck, F. P., Halliwell, B., Gan, Y.-H. The proteobacterial species Burkholderia pseudomallei produces ergothioneine, which enhances virulence in mammalian infection.

Selenocysteine as a Substrate, an Inhibitor and a Mechanistic Probe for Bacterial and Fungal Iron‐Dependent Sulfoxide Synthases

“…We have previously described the crystal structure of Cth EgtB and shown that this type of bacterial sulfoxide synthase accepts TMH and Cys as substrates . At neutral pH and at room temperature, Cth EgtB produces sulfoxide 3 as the main product (80 %) and cysteine dioxide as a minor product ( 6 , 20 %, Figure ).…”

Ergothioneine – a diet‐derived antioxidant with therapeutic potential

“…One of the most prominent of the ET-synthesising microorganisms is the pathogen, Mycobacterium tuberculosis, the causative agent of human tuberculosis [24, 97,98]. Indeed, inhibitors of the ET biosynthetic pathway (which should be a feasible therapeutic approach since this pathway does not occur in humans) could be a potential source of novel drugs to attack this and other pathogenic ET-synthesising organisms, such as that causing melioidosis [99]. One possibility is that M. tuberculosis not only makes ET but can also take it up from the environment (we have found that several bacteria can do this; our unpublished data); if the injury to the infected lung was to raise ET content in lung tissue (Fig.…”

“…From the properties of this molecule in vitro , antioxidant effects seem likely. However, other protective mechanisms may exist , and more work is required to elucidate them.…”

Ergothioneine, recent developments

“…[ [146] , [147] , [148] ] and Burkholderia spp. [ 149 ] belonging to the phyla Actinobacteria and Proteobacteria, respectively. They produce ET from histidine, albeit through distinct mechanisms [ 150 ].…”