# Targeted modification of the apramycin 2-deoxystreptamine ring to block aminoglycoside modifying enzyme-based inactivation and enhance potency against multidrug-resistant Gram-negative pathogens

> **NIH NIH R03** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $82,117

## Abstract

New antimicrobials are urgently needed to address the emergence of drug resistance in Gram-negative
pathogens. Apramycin is an aminocyclitol aminoglycoside that has impressive activity spectrum against
carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii, Pseudomonas aeruginosa, and
Staphylococcus aureus. In contrast to aminoglycosides such as plazomicin, it retains activity against strains
expressing widely circulating ribosomal methylases that are found at high frequency in 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 have demonstrated that apramycin is rapidly
bactericidal in vitro and in vivo in an A. baumannii murine thigh infection model. Importantly, there is only a
single known aminoglycoside modification enzyme (AME) in Gram-negatives, present in ~30% of CRE strains,
(extremely rare to absent in A. baumannii and P. aeruginosa), that inactivates apramycin through acetylation at
the C-3 amine position in the 2-deoxystreptamine (2-DOS) ring. Based on the underlying compelling properties
of apramycin, we propose to address the targeted hypothesis that combinatorial modification of 2-DOS will
block AME modification, thereby expanding activity spectrum, and increase potency, defined by lowering of the
minimal inhibitory concentrations against target Gram-negative pathogens and/or enhanced in vivo
antimicrobial exposure defined by preliminary snapshot pharmacokinetic indices. This exploration will be
accomplished in one specific aim, which will combine medicinal chemistry approaches with functional assays
to assess activity spectrum, potency, selectivity, and metabolism. 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 constraint on chemical space
available for exploration. The innovation of this proposal relies on use of a de novo total synthesis and novel
glyco-medicinal chemistry approaches to substitute 2-DOS variants into the apramycin scaffold. The near-term
goal of this two-year, exploratory R03 pilot proposal is to address potential of total synthetic glyco-medchem.
approaches to identify tractable, potent analogues worthy of further exploration. The long-term goal is to
develop apramycin analogues that have compelling properties as therapeutics against multidrug-resistant
pathogens.

## Key facts

- **NIH application ID:** 9868894
- **Project number:** 5R03AI144196-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** JAMES E KIRBY
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $82,117
- **Award type:** 5
- **Project period:** 2019-02-08 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868894

## Citation

> US National Institutes of Health, RePORTER application 9868894, Targeted modification of the apramycin 2-deoxystreptamine ring to block aminoglycoside modifying enzyme-based inactivation and enhance potency against multidrug-resistant Gram-negative pathogens (5R03AI144196-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868894. Licensed CC0.

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