# Role of NadD in Mycobacterium tuberculosis proteostasis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $254,250

## Abstract

Summary
The goal of this research program is to characterize the biology of NadD (nicotinate adenylyltransferase) from
Mycbobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). During infection, Mtb faces a
diverse set of host microenvironments and host chemistries that can lead to proteotoxic stress, including hypoxia,
mild acidity, metal starvation or intoxication, and reactive oxygen and nitrogen species. Antibiotic treatment of
TB patients can damage Mtb proteins by stalling nascent proteins on the ribosome or via the formation of reactive
oxygen or nitrogen intermediates. Many of these host stresses are associated with preventing or slowing of Mtb
replication and the development of non-genetic, phenotypic drug resistance. Mtb maintains protein integrity with
the proteostasis network – a collection of over one hundred proteins, including chaperones and their cofactors
(ClpB, DnaK, DnaJ1, DnaJ2, GrpE, GroEL/ES) and barrel-shaped proteases (ClpP1P2 and Mtb20S). The
transcription of many members of the proteostasis network is induced by proteotoxic stresses such as heat.
Genetic and chemical disruption of components of the proteostasis network is associated with decreased
virulence in macrophage and murine models of TB. We sought to identify compounds targeting components of
the proteostasis network by using a chemical screen for compounds whose activity was potentiated by a
proteotoxic stress generated by heat. Our characterization of one heat-stress potentiated compound
unexpectedly revealed NadD as the target. NadD is a high priority drug target that lies at a critical intersection of
de novo and salvage pathways for NAD(H) and NADP(H) biosynthesis. Chemical inhibition of NadD in wild-type
Mtb led to an increase in intrabacterial protein aggregation. We hypothesize that loss of NadD disrupts the
function of NADPH-dependent antioxidant defense systems and/or NadD plays a role as an unconventional
protein chaperone. This research takes two complementary directions: in Aim 1, we will use genetics and
chemical-biology to characterize NadD’s role in the proteostasis network, in particular by monitoring generation
of intrabacterial reactive oxygen and nitrogen species, protein carbonylation, and protein aggregation; and in
Aim 2, we will define the mechanism by which NadD contributes to Mtb proteostasis. These studies will lay the
groundwork to understand how NadD contributes as a noncanonical member of the proteostasis network during
infection and antibiotic treatment.

## Key facts

- **NIH application ID:** 10194900
- **Project number:** 1R21AI159572-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Benjamin S Gold
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2021-02-04 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194900

## Citation

> US National Institutes of Health, RePORTER application 10194900, Role of NadD in Mycobacterium tuberculosis proteostasis (1R21AI159572-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10194900. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*