# Targeting Cyclic Dinucleotide Signaling Pathways to Interrupt the Nature Cycle of Borrelia burgdorferi

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $659,925

## Abstract

Lyme disease has emerged as a major public health threat in the US. Currently, no human vaccine is available.
Although targeting tick populations with chemical acaricides is an effective way of reducing the risk of infection, the
use of acaricides has adverse health effects and raises environmental concerns. A host-targeted approach by
deploying doxycycline hyclate-laden baits to the field showed dramatic reduction of infection rates in both rodent
reservoirs and Ixodes scapularis ticks by Borrelia burgdorferi, the agent of Lyme disease. However, antibiotics such
as doxycycline are not suitable for such purpose as they are used for treating patients. Nevertheless, such proof of
concept study demonstrates that a host-targeted approach using alternative compounds is a promising approach to
eliminate spirochetes in rodent reservoir hosts and tick vectors. The bacterial second messengers, c-di-GMP and
c-di-AMP, have emerged as central regulators for bacterial physiology and are potential drug targets. Many bacteria
encode multiple copies of cyclases for the synthesis of c-di-GMP and c-di-AMP, which make it difficult to target
the pathways. Borrelia burgdorferi only has a single diguanylate cyclase Rrp1 and a single diadenylate cyclase
CdaA for c-di-AMP synthesis, which makes them attractive drug targets. As shown in the preliminary data, we found
that these two cyclic dinucleotide, one controls spirochetes’ survival in each of the two hosts in B. burgdorferi
enzootic cycle, ticks and mammals: while c-di-GMP is essential for tick colonization, c-di-AMP is indispensable for
mammalian infection. The hypothesis of this proposal is that small molecule inhibitors targeting c-di-GMP and c-di-
AMP cyclases, Rrp1 and CdaA, would eliminate B. burgdorferi in ticks and mammalian reservoirs, which can be
exploited to reduce Lyme disease incidence. The co-PI of this proposal, Dr. Herman Sintim, a Drug Discovery
Professor of Chemistry, pioneered developing inhibitors for bacterial diguanylate cyclase and diadenylate cyclase,
and his group has already reported several potent inhibitors against these cyclases of other bacteria. Accordingly,
we propose to develop a strategy to target CdaA of B. burgdorferi to eliminate in spirochetes rodent reservoirs (Aim
1), and a strategy to target Rrp1 of B. burgdorferi to eliminate spirochetes in ticks (Aim 2). We will also test a
combination of inhibitors targeting both pathways to eliminate B. burgdorferi in its enzootic cycle. The underlying
mechanisms of how c-di-AMP and c-di-GMP are employed by B. burgdorferi to survive in mammals and ticks will
also be investigate. This proposal address one of the specific Focus Areas listed in this RFA: reservoir-targeted
approaches to interrupt the natural history of infection. Upon accomplishing the proposed work, further field
experiments will be conducted using animal baits containing a combination of both inhibitors to evaluate their effects
on reducing spirochete burden in ticks and ...

## Key facts

- **NIH application ID:** 9990230
- **Project number:** 1R01AI152235-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Herman O Sintim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $659,925
- **Award type:** 1
- **Project period:** 2020-06-09 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990230

## Citation

> US National Institutes of Health, RePORTER application 9990230, Targeting Cyclic Dinucleotide Signaling Pathways to Interrupt the Nature Cycle of Borrelia burgdorferi (1R01AI152235-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990230. Licensed CC0.

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