A Role for the DtxR Family of Metalloregulators in Gram-positive Pathogenesis

Overview

Journal Mol Oral Microbiol

Specialties Dentistry
Microbiology

Date 2013 Sep 17

PMID 24034418

Citations 32

Authors

A T Merchant

G A Spatafora

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Bacterial Metallostasis: Metal Sensing, Metalloproteome Remodeling, and Metal Trafficking.

Capdevila D, Rondon J, Edmonds K, Rocchio J, Villarruel Dujovne M, Giedroc D Chem Rev. 2024; 124(24):13574-13659.

PMID: 39658019 PMC: 11672702. DOI: 10.1021/acs.chemrev.4c00264.

The role of transcriptional regulators in metal ion homeostasis of .

Wang S, Fang R, Wang H, Li X, Xing J, Li Z Front Cell Infect Microbiol. 2024; 14:1360880.

PMID: 38529472 PMC: 10961391. DOI: 10.3389/fcimb.2024.1360880.

TroR is the primary regulator of the iron homeostasis transcription network in the halophilic archaeon Haloferax volcanii.

Martinez Pastor M, Sakrikar S, Hwang S, Hackley R, Soborowski A, Maupin-Furlow J Nucleic Acids Res. 2023; 52(1):125-140.

PMID: 37994787 PMC: 10783522. DOI: 10.1093/nar/gkad997.

Pan-Genome-Wide Association Study of Serotype 19A Pneumococci Identifies Disease-Associated Genes.

Li T, Huang J, Yang S, Chen J, Yao Z, Zhong M Microbiol Spectr. 2023; 11(4):e0407322.

PMID: 37358412 PMC: 10433855. DOI: 10.1128/spectrum.04073-22.

The molecular mechanisms of the bacterial iron sensor IdeR.

Marcos-Torres F, Juniar L, Griese J Biochem Soc Trans. 2023; 51(3):1319-1329.

PMID: 37140254 PMC: 10317159. DOI: 10.1042/BST20221539.

References

Escolar L, Perez-Martin J, de Lorenzo V . Opening the iron box: transcriptional metalloregulation by the Fur protein. J Bacteriol. 1999; 181(20):6223-9. PMC: 103753. DOI: 10.1128/JB.181.20.6223-6229.1999. View

Wisedchaisri G, Holmes R, Hol W . Crystal structure of an IdeR-DNA complex reveals a conformational change in activated IdeR for base-specific interactions. J Mol Biol. 2004; 342(4):1155-69. DOI: 10.1016/j.jmb.2004.07.083. View

Boyd J, Oza M, Murphy J . Molecular cloning and DNA sequence analysis of a diphtheria tox iron-dependent regulatory element (dtxR) from Corynebacterium diphtheriae. Proc Natl Acad Sci U S A. 1990; 87(15):5968-72. PMC: 54451. DOI: 10.1073/pnas.87.15.5968. View

Posey J, Hardham J, Norris S, Gherardini F . Characterization of a manganese-dependent regulatory protein, TroR, from Treponema pallidum. Proc Natl Acad Sci U S A. 1999; 96(19):10887-92. PMC: 17978. DOI: 10.1073/pnas.96.19.10887. View

Burne R . Oral streptococci... products of their environment. J Dent Res. 1998; 77(3):445-52. DOI: 10.1177/00220345980770030301. View

Beres S, Richter E, Nagiec M, Sumby P, Porcella S, DeLeo F . Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus. Proc Natl Acad Sci U S A. 2006; 103(18):7059-64. PMC: 1459018. DOI: 10.1073/pnas.0510279103. View

Kehl-Fie T, Skaar E . Nutritional immunity beyond iron: a role for manganese and zinc. Curr Opin Chem Biol. 2009; 14(2):218-24. PMC: 2847644. DOI: 10.1016/j.cbpa.2009.11.008. View

Yellaboina S, Ranjan S, Chakhaiyar P, Hasnain S, Ranjan A . Prediction of DtxR regulon: identification of binding sites and operons controlled by Diphtheria toxin repressor in Corynebacterium diphtheriae. BMC Microbiol. 2004; 4:38. PMC: 524172. DOI: 10.1186/1471-2180-4-38. View

Olsen R, Sitkiewicz I, Ayeras A, Gonulal V, Cantu C, Beres S . Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis. Proc Natl Acad Sci U S A. 2010; 107(2):888-93. PMC: 2818956. DOI: 10.1073/pnas.0911811107. View

10.

Graham M, Smoot L, Migliaccio C, Virtaneva K, Sturdevant D, Porcella S . Virulence control in group A Streptococcus by a two-component gene regulatory system: global expression profiling and in vivo infection modeling. Proc Natl Acad Sci U S A. 2002; 99(21):13855-60. PMC: 129787. DOI: 10.1073/pnas.202353699. View

11.

Rappuoli R, Michel J, Murphy J . Integration of corynebacteriophages beta tox+, omega tox+, and gamma tox- into two attachment sites on the Corynebacterium diphtheriae chromosome. J Bacteriol. 1983; 153(3):1202-10. PMC: 221764. DOI: 10.1128/jb.153.3.1202-1210.1983. View

12.

Toukoki C, Gold K, McIver K, Eichenbaum Z . MtsR is a dual regulator that controls virulence genes and metabolic functions in addition to metal homeostasis in the group A streptococcus. Mol Microbiol. 2010; 76(4):971-89. PMC: 3082948. DOI: 10.1111/j.1365-2958.2010.07157.x. View

13.

Chicharro J, Serrano V, Urena R, Gutierrez A, Carvajal A, Fernandez-Hernando P . Trace elements and electrolytes in human resting mixed saliva after exercise. Br J Sports Med. 1999; 33(3):204-7. PMC: 1756161. DOI: 10.1136/bjsm.33.3.204. View

14.

Agranoff D, Krishna S . Metal ion homeostasis and intracellular parasitism. Mol Microbiol. 1998; 28(3):403-12. DOI: 10.1046/j.1365-2958.1998.00790.x. View

15.

Haswell J, Pruitt B, Cornacchione L, Coe C, Smith E, Spatafora G . Characterization of the functional domains of the SloR metalloregulatory protein in Streptococcus mutans. J Bacteriol. 2012; 195(1):126-34. PMC: 3536180. DOI: 10.1128/JB.01648-12. View

16.

Manabe Y, Saviola B, Sun L, Murphy J, Bishai W . Attenuation of virulence in Mycobacterium tuberculosis expressing a constitutively active iron repressor. Proc Natl Acad Sci U S A. 1999; 96(22):12844-8. PMC: 23125. DOI: 10.1073/pnas.96.22.12844. View

17.

Rolerson E, Swick A, Newlon L, Palmer C, Pan Y, Keeshan B . The SloR/Dlg metalloregulator modulates Streptococcus mutans virulence gene expression. J Bacteriol. 2006; 188(14):5033-44. PMC: 1539950. DOI: 10.1128/JB.00155-06. View

18.

Green I . Copper and manganese in saliva of children. J Dent Res. 1970; 49(4):776-82. DOI: 10.1177/00220345700490041201. View

19.

Bates C, Toukoki C, Neely M, Eichenbaum Z . Characterization of MtsR, a new metal regulator in group A streptococcus, involved in iron acquisition and virulence. Infect Immun. 2005; 73(9):5743-53. PMC: 1231137. DOI: 10.1128/IAI.73.9.5743-5753.2005. View

20.

Jakubovics N, Jenkinson H . Out of the iron age: new insights into the critical role of manganese homeostasis in bacteria. Microbiology (Reading). 2001; 147(Pt 7):1709-1718. DOI: 10.1099/00221287-147-7-1709. View