# Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $200,000

## Abstract

Tuberculosis (TB)—which is primarily caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb)—is
an ancient disease that remains one of the deadliest communicable diseases worldwide. A paramount concern
heading into the future is the rapid rise in drug-resistant TB. The World Health Organization estimated 480,000
cases of TB with 190,000 deaths in 2014 with resistance to the first-line anti-TB drugs isoniazid and rifampicin.
Furthermore, totally drug-resistant Mtb has now been documented in multiple countries including the United
States. The capuramycin family of glycosylated nucleoside antibiotics are excellent candidates for anti-TB drug
discovery and development because they (i) are considered new chemical entities with several unusual structural
features compared to all antibiotics including clinical anti-TB drugs, (ii) target a novel and essential enzyme
(translocase 1; TL1) in cell wall biosynthesis, (ii) have exceptional anti-Mtb activity in vitro and in vivo, (iv) are
bactericidal and kill Mtb faster than any first-line anti-TB drug in vitro, and (v) have no toxicity. Our primary
objectives in this proposal are to define a biosynthetic mechanism for the assembly of the unusual unsaturated
hexuronic acid component in capuramycins (Aim 1) and establish complementary chemical (via
neoglycorandomization; Aim 2) and biosynthetic (via native and nonnative glycosyltransferases; Aim 3) platforms
for rapidly generating novel hexuronic acid-substituted capuramycins that can be screened for TL1 inhibition,
anti-Mtb activity, and improved pharmacological properties. Additionally, these novel capuramycin analogues
will be screened as potential substrates or inhibitors of the phosphotransferase CapP, which covalently modifies
capuramycin as a strategy of self-resistance within the producing strain and is potentially a widespread
resistance mechanism. It is expected that, upon completion of the aims, a new biosynthetic mechanism for sugar
incorporation and modification will be defined. Furthermore, the completion of the aims will provide the first
practical, comprehensive strategy to rapidly interrogate/modulate the fundamental features of capuramycin core
pharmacophore, which will not only be important for the clinical development of capuramycin but can be applied
to other glycosylated nucleoside antibiotics, of which dozens are now known with diverse biological activities.

## Key facts

- **NIH application ID:** 9838717
- **Project number:** 5R01AI128862-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Jon Scott Thorson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838717

## Citation

> US National Institutes of Health, RePORTER application 9838717, Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics (5R01AI128862-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838717. Licensed CC0.

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