# Bulgecin Template for Potentiation of beta-Lactam Antibiotics

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2022 · $629,042

## Abstract

Project Summary/Abstract
Gram-negative bacteria have become broadly resistant to known classes of antibiotics. Treatment of infections
by these pathogens has become increasingly challenging and efforts in the past two decades in discoveries of
new classes of antibacterial agents have failed. In this grant application, we have turned our attention to
bulgecins, a group of three natural products (bulgecins A, B and C) discovered in the 1980s, which potentiate
the activities of b-lactam antibiotics to Gram-negative bacteria. The three natural products were prepared by
total synthesis and we documented the potentiation activity in microbiological experiments. Furthermore, we
documented by both fluorescence microscopy and by scanning-electron microscopy that the combination of
bulgecin A and a b-lactam antibiotic (ceftazidime or meropenem) cause bulges in the bacterial envelope, which
are points of structural instability that burst and lead to bactericidal effect. In addition, we documented that
merely two lytic transglycosylases out of 11 in Pseudomonas aeruginosa—Slt and MltD (with ceftazidime) and
Slt and MltG (with meropenem)—are the targets of bulgecin A. We also report the X-ray structure for the
complex of Slt with bulgecin A. We disclose the next phase of this research in two Specific Aims. Specific Aim
1 addresses our planned analysis of the bulgecin-biosynthetic cluster, which we discovered recently. The
eight-gene cluster converts L-serine and L-aspartic acid to bulgecinine, a key structural component of
bulgecins, and then in turn, to bulgecins A, B and C. We propose to study these genes both for their
enzymological reactions and for their structures. A proposal is outlined to prepare the high-value bulgecinine
using a host bacterium as a “one-pot” reaction vessel. We already have reported a chemical synthesis for
bulgecinine and a second (shorter) synthetic approach is also proposed. A detailed plan is outlined in Specific
Aim 2 to optimize the bulgecin template. The process takes advantage of our X-ray structure for the complex of
Slt and bulgecin A in a computational analysis to identify analogs that will bind more potently to lytic
transglycosynases and achieve penetration into Gram-negatives more avidly. The proposed targets will be
synthesized and fully analyzed in a series of both in vitro and in vivo experiments in identification of a suitable
combination of a bulgecin analog with a b-lactam antibiotic in fighting Gram-negative bacterial infections.

## Key facts

- **NIH application ID:** 10438764
- **Project number:** 5R01AI148217-03
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Shahriar Mobashery
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $629,042
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438764

## Citation

> US National Institutes of Health, RePORTER application 10438764, Bulgecin Template for Potentiation of beta-Lactam Antibiotics (5R01AI148217-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438764. Licensed CC0.

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