# Apramycin scaffold exploration using novel glycochemistry and SAR studies to enhance activity against Acinetobacter baumannii and other multidrug-resistant Gram-negative pathogens

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $210,119

## Abstract

Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae are
emerging multidrug-resistant Gram-negative bacterial pathogens. With increasing frequency, they often prove
untreatable or treatable only with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in
their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. Apramycin is an
aminocyclitol aminoglycoside that has impressive activity spectrum against these pathogens. Further, in
contrast to plazomycin, it retains activity against strains expressing widely circulating ribosomal methylases
that for example are often found in the alarmingly multidrug-resistant, NDM-1 carbapenemase strains.
Importantly, apramycin also does not appear to have significant nephrotoxicity and ototoxicity side effects that
have limited clinical use of other aminoglycosides. We also found that apramycin showed rapid bactericidal
killing, high selectivity for prokaryotic ribosomes, and efficacy against A. baumannii in a murine thigh infection
model. Based on such compelling properties, we propose to pursue medicinal chemistry based optimization of
the apramycin scaffold in two specific aims: The first goal is to perform structure-activity relationship and
structure-pharmacokinetic relationship studies to identify derivatives with enhanced antimicrobial potency while
maintaining selectivity. In the past, medicinal chemistry evaluation of the apramycin scaffold made use of semi-
synthetic approaches based on modification of the existing apramycin natural product. These approaches
necessarily placed significant constraints on chemical space available for exploration. Here, we hypothesize
that use of modern, total synthetic glycochemistry approaches will allow us to optimize and develop
compelling therapeutic leads with activity against Acinetobacter and other resistant Gram-negative organisms.
The second proof-of-principle goal will be to characterize the ability of apramycin analogues to treat XDR
Acinetobacter infection in a murine thigh infection model. Experiments will also address whole animal toxicities
and iterate back into the medicinal chemistry optimization plan with the long-term goal of developing safe and
effective therapy. The near-term goal of this two year, exploratory R21 proposal is to address potential of total
synthetic glycochemistry approaches to identify tractable, potent analogues worthy of further exploration.

## Key facts

- **NIH application ID:** 9822169
- **Project number:** 5R21AI142040-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** JAMES E KIRBY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $210,119
- **Award type:** 5
- **Project period:** 2018-11-13 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9822169

## Citation

> US National Institutes of Health, RePORTER application 9822169, Apramycin scaffold exploration using novel glycochemistry and SAR studies to enhance activity against Acinetobacter baumannii and other multidrug-resistant Gram-negative pathogens (5R21AI142040-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9822169. Licensed CC0.

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