# Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $183,415

## Abstract

Project Summary/Abstract: Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate
 New antibiotics are desperately needed against drug-resistant Gram-positive pathogens, such as methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). This proposal seeks to
synthesize and validate aza-Novo29 as a new antibiotic candidate against Gram-positive pathogens that is stable
toward hydrolysis. The proposal is based on the findings that the recently discovered antibiotic Novo29 shows
promising antibiotic activity but is hydrolytically unstable at physiological pH. The central hypothesis that will be
tested in the current proposal, is that the macrolactam analogue of Novo29 — aza-Novo29 — will exhibit good
activity against Gram-positive pathogens but will not suffer hydrolysis at physiological pH.
 The proposal builds upon studies of analogues of the related antibiotic teixobactin. These studies have
established that a macrolactam analogue of teixobactin not only tolerates replacement of the macrolactone ring
with a macrolactam ring, but actually exhibits 2–8-fold greater antibiotic activity. The proposal also builds upon
the concept that lactams are far more resistant to hydrolysis than lactones. In combination, these observations
suggest that aza-Novo29 will exhibit good antibiotic activity but resist hydrolysis.
 Novo29 contains a non-proteinogenic β-hydroxyasparagine residue. The stereochemistry of this β-
hydroxyasparagine residue is not known. As part of the proposed studies, the stereochemistry of the β-
hydroxyasparagine residue will be determined through chemical synthesis and correlation with authentic
Novo29.
 There are three specific aims: (1) To develop a synthesis of Novo29 in order to assign its stereochemistry by
spectroscopic comparison to authentic Novo29 and side-by-side comparison in antibiotic activity assays. (2) To
develop a synthesis of aza-Novo29, the lactam analogue of Novo29. (3) To determine whether aza-Novo29 has
good activity against Gram-positive pathogens, while having improved hydrolytic stability compared to Novo29.
 The expected outcome is the creation of aza-Novo29 as a promising antibiotic candidate for further drug
development. It is expected that aza-Novo29 will exhibit good activity against MRSA and VRE, as well as
resistance to hydrolysis under the conditions needed for intravenous administration. The results of this research
will impact the field of antibiotics by developing and expanding upon the newly discovered antibiotic class that
includes teixobactin and Novo29. The success of this project will pave the way for further development of aza-
Novo29 as a preclinical antibiotic candidate.

## Key facts

- **NIH application ID:** 10624354
- **Project number:** 5R21AI168966-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** JAMES S NOWICK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $183,415
- **Award type:** 5
- **Project period:** 2022-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10624354

## Citation

> US National Institutes of Health, RePORTER application 10624354, Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate (5R21AI168966-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10624354. Licensed CC0.

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