Public Health Research Institute Center and
UMDNJ - New Jersey Medical School
225 Warren Street
Newark, New Jersey 07103

Phone: (973) 854-3262
e-mail: rodrigg2@umdnj.edu



Research Summary

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), continues to claim the lives of millions of people worldwide. New drugs and a more efficient vaccine are urgently needed. Mtb is a facultative intracellular pathogen that replicates in macrophages and extracellularly, in lung cavities. During infection, Mtb is exposed to different environments and stress conditions to which it must adapt in order to survive and multiply. Iron deficiency is one of those conditions. As is the case for most living organisms, Mtb requires iron for vital cellular functions. Due to the poor aqueous solubility of ferric ion in the presence of oxygen and at neutral pH, free iron is not found in the mammalian host, but is sequestered in complexes with iron binding glycoproteins or bound to protoporphyrins in heme and hemoproteins. Furthermore, as a defensive response to infection, the host withholds iron from blood and tissues, thus further limiting iron availability to the pathogen. Like all successful pathogens, Mtb is able to compete for iron in the host through the expression of specialized iron sequestration and transport systems. It has been recognized that iron availability influences the severity of tuberculosis and that abnormally high levels of iron in Mtb infected humans and animal models are associated with exacerbation of the disease. Based on these observations we believe that iron acquisition and the proteins involved in this process are good targets for therapeutic intervention or prevention of TB. In this context the goals of the projects going on in the laboratory are:

1. Understanding the complex process by which Mtb acquires iron. Mtb synthesizes and secretes siderophore molecules that can chelate ferric iron from the environment. Fe+3-siderophore complexes are transported inside the cell by a process that is not completely understood. We have identified an ABC-transporter (IrtAB) essential for iron uptake in Mtb (Figure 1), but other molecules involved in iron uptake and the functional interactions between them remain to be discovered.

2. Characterizing the regulatory mechanisms involved in the adaptive response of Mtb to iron deficient conditions encountered in the host. We wish to understand the adaptive response of Mtb to iron availability in the host. This response is controlled by the essential iron dpendnet transcriptional regulator IdeR (Figure 1) and includes the induction of iron acquisition systems, the global adjustment of basic metabolism and the expression of virulence determinants. We believe that understanding this response and how it is regulated will reveal potential targets to interfere with survival of Mtb in an infected host.

3. Applying the knowledge derived from our basic studies to the development of new therapeutic or preventive tools against M. tuberculosis.

Figure 1. Siderophore mediated iron acquisition in M. tuberculosis. M. tuberculosis facing iron deficiency secretes siderophores called carboxymycobactins (CM) which chelate Fe+3. Fe+3-CM complexes are transported into the cell by the iron regulated ABC-transporter IrtAB. In the cytoplasm the amino terminal domain of IrtA binds FAD and may reduce Fe+3 in the Fe+3-CM complex to release Fe+2 for utilization and storage. Iron metabolism is controlled by the iron dependent regulator IdeR, which under conditions of iron sufficiency binds iron and represses transcription of siderophore synthesis and transport genes repressing iron uptake, while induces transcription of the iron storage genes bfrA and bfrB.




Recent Articles


Madigan C.A., Cheng T.Y., Layre E., Young D.C., McConnell M.J., Dbono C.A., Murry J.P., Wei J.R., Barry C.E. 3rd, Rodriguez G.M., Matsunaga I., Rubin I., Moody D.B. 2012
Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis.
PNAS.

Santhanagopalan S.M., Rodriguez G.M. 2011
Examining the role of Rv2895c (ViuB) in iron acquisition in Mycobacterium tuberculosis.
Tuberculosis.

Ryndak, M. B., Wang, S., Smith, I., Rodriguez, G. M. 2010
Mycobacterium tuberculosis high affinity iron importer, IrtA, contains an FAD2 binding domain.
Journal of Bacteriology. 192: 861-869

Janagama H. K., Senthikumar T. M., Bannantine J. P. Rodriguez G. M., Smith I., Paustian M. L., McGarvey J. A., Sreevatsan S. 2009
Identification and functional characterization of the iron-dependent regulator (IdeR) of mycobacterium avium subsp. Paratuberculosis.
Microbiology. 155:3683-90

Rao, P. K., Rodriguez, G. M., Smith, I., Li, Q. 2008
Protein dynamics in iron-starved Mycobacterium tuberculosis revealed by turnover and abundance measurement using hybrid-linear ion trap-Fourier transform mass spectrometry.
Anal. Chem. 80:6860-9

Rodriguez G.M, Gardner R, Kaur N, Phanstiel O. IV. 2008
Utilization of Fe3+-Acinetoferrin analogues as iron source by Mycobacterium tuberculosis.
BioMetals. 21:93-103.

Maciag A., Dainese E, Rodriguez G.M., Milano A, Provvedi R, Pasca MR, Smith I, Palu G, Riccardi A and Manganelli R. 2007
Global analysis of Mycobacterium tuberculosis Zur(FurB) regulon.
J. Bacteriol.. 189:730-740.

Rodriguez, G.M and Smith, I., 2006
Identification of an ABC transporter Required for Iron acquisition in Mycobacterium tuberculosis.
Journal of Bacteriology 188: 424-430.8.

Rodriguez, G.M. 2006
Control of Iron Metabolism in Mycobacterium tuberculosis.
Trends in Microbiology. 14;320-327

Rodriguez, G.M and Smith, I. 2004
Iron Metabolism in Pathogenic Bacteria
in “Iron transport in Bacteria: Molecular Genetics, Biochemistry, Microbial Pathogenesis and Ecology”. (Eds. J. Crosa & S. Payne) ASM Press.

Rodriguez, G.M., Voskuil, M.I., Gold, B., Schoolnik, G.K, and Smith, I. 2002
IdeR, an essential gene in Mycobacterium tuberculosis: Role of IdeR in Iron-dependent gene expression, iron metabolism and oxidative stress response.
Infection and Immunity. 7:3371-3381.

Gold, B.,Rodriguez, G.M., Marras, S, Pentecost, M., Smith, I. (2001)
The Mycobacterium tuberculosis IdeR is a dual functional regulator that controls transcription of genes involved in iron acquisition, iron storage and intracellular survival in macrophages.
Molecular Microbiology. 42:851:865.

Rodriguez, G.M. and Smith I. 2003
Mechanisms of iron regulation in mycobacteria: role in physiology and virulence.
Review. Molecular Microbiology. 47:1485-1494.

Rodriguez, G.M, Gold, B., Gomez, M., Dussurget, O., and Smith I. 1999
Identification and characterization of two divergently transcribed iron regulated genes in Mycobacterium tuberculosis.
Tubercle and Lung disease.; 79:287-298.