# De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $815,399

## Abstract

There is an emerging threat from multidrug-resistant Gram-negative bacterial pathogens, specifically,
carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa (e.g.,
ESKAPE pathogens). The resulting infections are often untreatable or treatable only with toxic
antimicrobials. More troubling is the fact that the incidences of these infections are occurring with increasing
frequency. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat
level. New anti-infective strategies are urgently needed. This multi-PI R01 application proposes a de novo
medicinal chemistry design and de novo carbohydrate synthesis approach, which when coupled with
functional characterization and cryo-EM enabled structure-guided design should lead to the rapid discovery
of novel aminoglycoside (AG) antimicrobials with activity against resistant Gram-negative pathogens.
The long-term expected outcomes are 1) the establishment of new synthetic methodology for systematic
medicinal chemistry SAR-based exploration of the aminoglycoside chemical space and 2) the discovery of
new aminoglycoside structural motifs with improved activity against resistant bacteria (e.g., AME, RMT-
mediated resistance). The underlying hypothesis that guides our approach is the assumption that there are
many carbohydrate structures that remain undiscovered due to the synthetic limitations of traditional
carbohydrate and semi-synthetic approaches. In contrast, our total de novo synthetic approach enables the
installation of a much broader range of carbohydrates in a stereochemically selective manner. Examples of
structural variations that will be explored are aminoglycosides with rare aminosugar, linear sugar, and 2-
deoxystreptamine (2-DOS) substitutions that are designed to evade known aminoglycoside resistance
mechanisms.

## Key facts

- **NIH application ID:** 10072097
- **Project number:** 1R01AI154860-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** JAMES E KIRBY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $815,399
- **Award type:** 1
- **Project period:** 2020-08-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072097

## Citation

> US National Institutes of Health, RePORTER application 10072097, De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity (1R01AI154860-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072097. Licensed CC0.

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