# Biosynthesis of nucleoside antibiotics targeting bacterial translocase I

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $373,108

## Abstract

New antibiotics are needed, particularly those that can be considered as new chemical entities
and have novel targets relative to the current, clinical armament of antibiotics. Highly modified
nucleoside antibiotics that inhibit bacterial translocase I (TL1) involved in cell wall biosynthesis fit
both these descriptions, and have excellent potential in part because they are (i) nanomolar
inhibitors of TL1, (ii) inhibit a target that has been proven to be essential for the survival of most,
if not all, bacteria, (iii) are effective antibiotics in both in vitro and in vivo models, and (iv) have no
apparent toxicity in mice. We have defined the biosynthetic mechanism leading to the core
disaccharyl-nucleoside structure of several promising nucleoside antibiotics including A-90289
from Streptomyces sp. SANK 60405, muraminomicin from Streptosporangium sp, and
muraymycin from Streptomyces sp. LL-AA896 using a combined in vivo and in vitro approach.
The results have defined a multi-enzyme pathway highlighted by divergence from the primary
building block UMP and reconvergence to form the core nucleoside. This data was utilized to scan
the wealth of genomic information to identify a new lead antibiotic, sphaerimicin, which was
isolated and revealed to share the nucleoside core structure but have several unique features
including a dihydroxylated piperidine ring of unknown origin. We will now accomplish the following
specific aims: (i) to define the mechanism for the attachment of the 3-amino-3-carboxypropyl
(3A3CP) moiety that generates the last, shared intermediate in the biosynthesis of A-90289,
muraminomicin, muraymycin, and sphaerimicin, which is hypothesized to occur via a new enzyme
strategy catalyzed by a pyridoxal-5′-phosphate-dependent protein and (ii) to delineate the
biosynthetic mechanism for divergence from the last, shared intermediate to generate unique,
nucleoside core scaffolds that are further decorated by fatty acids, polyketides, nonribosomal
peptides, and/or saccharides. A biosynthetic mechanism for the diazepanone ring for A-90289
and the highly unusual fused piperidine ring system in sphaerimicin will be defined.

## Key facts

- **NIH application ID:** 9903243
- **Project number:** 5R01AI087849-09
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Steven Gary Van Lanen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,108
- **Award type:** 5
- **Project period:** 2011-06-15 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903243

## Citation

> US National Institutes of Health, RePORTER application 9903243, Biosynthesis of nucleoside antibiotics targeting bacterial translocase I (5R01AI087849-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9903243. Licensed CC0.

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