A role for the DtxR family of metalloregulators in gram‐positive pathogenesis

Abstract

SUMMARY Given the central role of transition metal ions in a variety of biochemical processes, the colonization, survival, and proliferation of a bacterium within a host hinges upon its ability to overcome the metal ion deprivation that characterizes nutritional immunity. Metalloregulatory, or “metal-sensing” proteins have evolved in bacteria to mediate metal ion homeostasis by activating or repressing the expression of genes encoding metal ion transport systems upon binding their cognate metal ion. Yet increasing evidence in the literature supports an additional role for these metalloregulatory proteins in pathogenesis. Herein, we survey studies on the DtxR family of metalloregulators, namely DtxR (Cornyebacterium diphtheriae), SloR (Streptococcus mutans), MtsR (Streptococcus pyogenes), and MntR (Staphylococcus aureus) to describe how metalloregulation enables adaptive virulence gene expression within the mammalian host. This research has important implications for drug design, as the generation of hyper-repressive metalloregulatory proteins may represent a mechanism by which to attenuate bacterial pathogenicity. The fact that metalloregulators are unique to prokaryotes makes these proteins especially attractive therapeutic targets.

Manganese uptake and streptococcal virulence

“…It has been demonstrated that transcription of genes encoding Mn 2+ -specific SBPs in multiple streptococcal species is repressed by Mn 2+ (Crump et al 2014; Merchant and Spatafora 2014; Ogunniyi et al 2010). In each case, this repression is mediated by a MntR-like protein often encoded within the ABC transporter operon or nearby.…”

Stress Physiology of Lactic Acid Bacteria

“…This effect may partly explain the increase of expression of scaCBA in the presence of toxic levels of Zn 2ϩ (85) (88). Later studies showed that SloR controls a large regulon, acting both as a repressor and as an activator (69,89). The homologous regulator MtsR of S. pyogenes also controls a large regulon that includes the genes encoding the Mn 2ϩ and Fe 2ϩ transporter MtsABC (90,91).…”

“…Resistance mechanisms against metals are not well characterized for LAB (reviewed in reference 26), and most available information concerns pathogenic streptococci. In bacteria, three types of metalsensing transcriptional regulators control gene expression in response to metal ion concentrations: derepressors (ArsR-SmtB, CopY, and CsoR-RcnR families), activators (MerR family), and corepressors (Fur, NikR, and DtxR families) (69).…”

“…Regulators of the DtxR/MntR family are metal sensors that usually bind Fe 2ϩ or Mn 2ϩ (69). Cytoplasmic manganese plays a significant role in the protection against oxidative stress in LAB (83).…”

DNA Sequence Analysis of dtxR Gene (Partial) of Corynebacterium diphtheriae Causing Diphtheria in Jawa and Kalimantan Islands, Indonesia

“…(12,13) The dtxR gene is also referred as a global regulator or metalloregulator as its function in regulating several genes involved in iron uptake and transport, including Siderophore or Corynebactin. (14,15) The DtxR is a 25 kDa protein that consists of 226 amino acid residues. DtxR proteins are divided into three domains, helix-turn-helix (residues 1-73), metal binding site (residues 74-140), and Src homology 3 (SH-3) (residues 147-226).…”