# Platforms for the Synthesis of Bacterial Protein Synthesis Inhibitors

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $403,750

## Abstract

Project Summary/Abstract
Only two new structural classes of antibiotics, exemplified by daptomycin and linezolid, have been introduced
to the market in the past 50 years. This dearth of novel antibiotics is not due to lack of new chemical matter;
indeed, dozens or even hundreds of molecules with antimicrobial activity are discovered annually, but the
majority of these are not suitable for deployment as human therapeutics. Additionally, many of the antibiotics
on the market have undesirable properties (e.g., toxicity, chemical instability, metabolic liabilities) that deter
physicians from employing them. The high degree of structural complexity present in most of these molecules
complicates medicinal chemistry efforts to improve their properties. Our laboratory seeks to address this
challenge by developing modular strategies for the assembly of structurally complex classes of antibiotics that
have not yet reached their potential as therapeutics. Unlike many total synthesis proposals, our primary goal is
not to develop methods for the synthesis of natural products (although this can be accomplished with our
approach), but rather to use their structural architectures to guide the development of new structural classes.
During our first 2 years in operation, we have developed a modular, scalable synthesis of streptogramin
antibiotics (J. Am. Chem. Soc. 2017, doi: 10.1021/jacs.7b08577), and we have made significant headway
towards a practical synthesis of lankacidin antibiotics. With these preliminary results as groundwork, five years
of NIGMS MIRA funding will enable the development structurally novel therapeutics based on these classes
that have improved physicochemical properties, broader spectra of activity, and increased activity against
multidrug-resistant strains of bacteria. This pursuit will be facilitated by chemical and biological innovations with
broad applicability. We also propose a method for binding-induced hybridization of therapeutics that we believe
will find use beyond the application to ribosome-targeting antibiotics. Our efforts will be enabled by strategic
collaborations to enable crystallographic characterization of the binding interactions of our analogs (with Prof.
Yury Polikanov, UIC) and to evaluate the efficacy of antibiotic candidates against a broad panel of bacterial
pathogens, including many multi-drug resistant strains (with Dr. Dean Shinabarger, Micromyx).
This research program is significant because it has the potential to expand the frontiers of chemical reactivity,
to facilitate discoveries in structural biology, and to address an urgent unmet medical need.

## Key facts

- **NIH application ID:** 9978836
- **Project number:** 5R35GM128656-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ian Bass Seiple
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978836

## Citation

> US National Institutes of Health, RePORTER application 9978836, Platforms for the Synthesis of Bacterial Protein Synthesis Inhibitors (5R35GM128656-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978836. Licensed CC0.

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