Treponema pallidum (Tp), the causative agent of syphilis, is one of most poorly understood of all bacterial pathogens. That Tp cannot be cultivated continuously in vitro has severely hampered progress towards understanding many of the complexities associated with Tp membrane biology and syphilis pathogenesis. Tp encodes a large number of membrane lipoproteins (LPs) that have widespread importance. Over the past funding interval, we have pursued a structural biology approach for characterizing the Tp LPs by solving their three-dimensional structures and then testing hypotheses about their possible functions. We now have compelling evidence that this unconventional approach represents a successful discovery platform. First, we have described in Tp a periplasmic transport system comprised of two LPs (TP0956/TP0957) that make up a TPR-protein-associated TRAP transport system. This system has many molecular features never before described for a bacterial transport apparatus. TP0956/TP0957 forms a complex that spans precisely the width of the Tp periplasm, and which contains a hydrophobic pore; we shall attempt to determine the ligand carried by this transport complex (Aim 3). We also have identified an essential ABC-type of riboflavin transporter (RfuABCD) in pathogenic spirochetes. This type of riboflavin transport system has never been previously described in bacteria, but it has prompted a re-examination of the potential importance of flavin-containing cofactors and flavoproteins to Tp biology. We also have discovered in Tp a novel FAD pyrophosphatase (TP0796/Ftp), the first such recognition of this type of enzymatic activity in any bacterium; the discovery has further implications for flavin utilization/homeostasis in Tp and, along with our other findings, engenders a new conception that Tp has evolved a flavin-centric lifestyle. Indeed, we have found that Tp encodes a homolog of RnfD (TP0151) that, in other bacteria, requires FMN as a co-factor and typically is a member of an RnfABCDGE operon for redox-driven ion pumps. Tp has been thought NOT to encode such as system, but we also have found a homolog of RnfC (TP0152) (within the gene cluster tp0147-tp0153). These combined findings engender strong supposition that Tp encodes a complete Rnf redox system, something that challenges existing dogma. Establishing that one or more of these Rnf-like proteins interact with each other will provide further evidence of an active Rnf-like redox system in Tp (Aim 2). A better understanding of this flavin-centric lifestyle for Tp may result in valuable new intervention strategies that target eiher riboflavin uptake or flavin utilization pathways, and could also provide further nutritional information leading to the eventual in vitro cultivation of Tp (Aim 1). Finally, all of our discoveies underscore the power of our structure-to-function approach, and thus we anticipate many more new advancements from discerning the structures of the Tp LPs (Aim 4.).

Public Health Relevance

Syphilis, caused by the bacterium Treponema pallidum, continues to play prominently as a sexually transmitted infection in the United States and worldwide. The membrane lipoproteins of T. pallidum are recognized as being particularly vital to the biology of the spirochete. Given their importance, we are targeting these molecules for strategic study. Discerning the functions of T. pallidum's membrane lipoproteins can potentially help to explain many of the salient features of T. pallidum's peculiar membrane biology, elucidate key aspects of the spirochete's parasitic strategy, prompt new modalities to thwart the infectious process, and spawn new avenues of investigation for potentially designing novel antimicrobial drugs.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Bacterial Pathogenesis Study Section (BACP)
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Hiltke, Thomas J
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University of Texas Sw Medical Center Dallas
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Deka, Ranjit K; Liu, Wei Z; Tso, Shih-Chia et al. (2018) Biophysical insights into a highly selective l-arginine-binding lipoprotein of a pathogenic treponeme. Protein Sci 27:2037-2050
Brautigam, Chad A; Deka, Ranjit K; Liu, Wei Z et al. (2017) Functional clues from the crystal structure of an orphan periplasmic ligand-binding protein from Treponema pallidum. Protein Sci 26:847-856
Radolf, Justin D; Deka, Ranjit K; Anand, Arvind et al. (2016) Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nat Rev Microbiol 14:744-759
Brautigam, Chad A; Deka, Ranjit K; Liu, Wei Z et al. (2016) The Tp0684 (MglB-2) Lipoprotein of Treponema pallidum: A Glucose-Binding Protein with Divergent Topology. PLoS One 11:e0161022
Deka, Ranjit K; Brautigam, Chad A; Liu, Wei Z et al. (2016) Molecular insights into the enzymatic diversity of flavin-trafficking protein (Ftp; formerly ApbE) in flavoprotein biogenesis in the bacterial periplasm. Microbiologyopen 5:21-38
Brautigam, Chad A; Deka, Ranjit K; Liu, Wei Z et al. (2015) Insights into the potential function and membrane organization of the TP0435 (Tp17) lipoprotein from Treponema pallidum derived from structural and biophysical analyses. Protein Sci 24:11-9
Bashiri, Ghader; Baker, Edward N (2015) Production of recombinant proteins in Mycobacterium smegmatis for structural and functional studies. Protein Sci 24:1-10
Deka, Ranjit K; Brautigam, Chad A; Liu, Wei Z et al. (2015) Evidence for Posttranslational Protein Flavinylation in the Syphilis Spirochete Treponema pallidum: Structural and Biochemical Insights from the Catalytic Core of a Periplasmic Flavin-Trafficking Protein. MBio 6:e00519-15
Scheuermann, Thomas H; Brautigam, Chad A (2015) High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC. Methods 76:87-98
Brautigam, Chad A (2015) Fitting two- and three-site binding models to isothermal titration calorimetric data. Methods 76:124-136

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