# The flavin-centric metabolic lifestyle of Treponema pallidum

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $541,032

## Abstract

Project Summary/Abstract
Despite its historical importance as a plague on humankind, syphilis remains among the most poorly
understood of all human infections. This is a direct result of severe research constraints imposed by the
historic inability to cultivate Treponema pallidum (Tp) continuously in vitro. In a departure from more
conventional approaches, about 15 years ago we embarked on a bold structural biology-based initiative to
characterize Tp’s lipoproteins (LPs), molecules critical to the membrane biology, bioenergetics, and
intermediary metabolism of Tp, as a means of unlocking the mechanistic evolutionary “secrets” of Tp
infection and syphilis pathogenesis. This progressive research avenue has become a very successful
discovery platform, yielding many highly novel findings, including establishing a number of new bacterial
molecular paradigms. For example, we discovered a novel bi-functional FAD pyrophosphatase/FMN
transferase in Tp; this, in turn, led us to identify a post-translational protein flavinylation pathway in Tp’s
periplasm, yielding flavoproteins that ostensibly influence cellular redox reactions. We then obtained
evidence for Tp encoding an atypical flavin-based Rhodobacter Nitrogen Fixation (RNF)-type redox pump,
likely representing the longstanding missing link between Tp’s membrane electrochemical gradient, redox
balance, ATP generation, and an acetogenic energy conservation pathway. Historically, Tp has been
thought not to encode such systems. Our contention of a flavin-based redox system not only addresses a
number of longstanding unexplained metabolic dilemmas for Tp, but it also engenders a paradigm shift by
now establishing Tp as a flavin auxotroph. We also have demonstrated that TP0572, a putative FMN-
dependent ferric reductase, is flavinylated by Ftp (TP0796), likely an essential prerequisite for Tp’s
reductive iron assimilation pathway(s). In addition, predicted cytosolic flavoproteins must play prominently
in protecting Tp from oxidative stress and in maintaining the balance of NAD+/NADH. These collective
notions support that, with limited potential for ATP generation in the absence of quinones, Tp has evolved
a “flavin-centric metabolic lifestyle” to fulfill its metabolic requirements for human infection. This project
shall address three core metabolic features relevant to Tp’s flavin biology: protein flavinylation and
flavoprotein biogenesis (Aim 1), reductive iron assimilation and Fe-S protein biogenesis (Aim 2), and redox
balance/energy conservation (via acetogenesis) (Aim 3). We also shall evaluate a small-molecule
inhibitor(s) targeting Tp’s flavin auxotrophy as a potential new research tool(s) and/or new
antimicrobial(s) against Tp and other pathogenic spirochetes (Aim 4). Taken together, this project shall
elucidate key features concerning how Tp has evolved to exploit flavins as an underpinning of its stealth
pathogenicity, potentially leading to new strategies to thwart human infection.

## Key facts

- **NIH application ID:** 9882189
- **Project number:** 2R01AI056305-16A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** MICHAEL V. NORGARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $541,032
- **Award type:** 2
- **Project period:** 2003-07-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882189

## Citation

> US National Institutes of Health, RePORTER application 9882189, The flavin-centric metabolic lifestyle of Treponema pallidum (2R01AI056305-16A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882189. Licensed CC0.

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