# Development of Streptothricin Class Antimicrobials as Novel Therapeutics

> **NIH NIH R21** · NORTHEASTERN UNIVERSITY · 2020 · $248,169

## Abstract

Acinetobacter baumannii and carbapenem-resistant Enterobacteriaceae are among an emerging class of
multidrug-resistant, Gram-negative bacterial pathogens that are often either effectively untreatable or only
treatable with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibiotic
resistance threat level. New anti-infective strategies are urgently needed. Streptothricin is an antibiotic that was
discovered over 70 years ago. It has an impressive activity spectrum against otherwise resistant Gram-negative
pathogens. However, initial concern around toxicities and the availability of alternative antibiotics precluded its
development, and it has largely been forgotten. Moreover, in the past, when it was still considered the basis of
a potential therapeutic, molecular optimization approaches were limited to semi-synthetic approaches based on
modification of the already existing natural product, severely limiting exploration of potential chemical space.
However, we hypothesize based on the availability of modern total synthetic approaches that the streptothricin
scaffold can be modified to optimize its properties and develop a much needed therapeutic with activity against
Acinetobacter and other resistant Gram-negative organisms. Preliminary data is presented that shows selectivity
for prokaryotic ribosomes, rapid bactericidal killing, extended in vitro activity spectrum against A. baumannii, and
efficacy against A. baumannii in a murine thigh infection model. Furthermore, support for a total convergent
synthetic strategy is presented, which for the first time will allow full exploration of the streptothricin scaffold.
Based on these compelling preliminary data and streptothricin's intrinsic antimicrobial activity, two specific goals
will be pursued. The first is to perform structure-activity relationship studies to identify derivatives with
significantly enhanced prokaryotic selectivity and nonsusceptibility to streptothricin acetyltransferase-based
inactivation, while maintaining activity spectrum and potency. Additional properties will also be examined and
addressed where possible, such as Gram-negative bacterial penetrance, efflux, and metabolic stability. The
second goal will be to characterize the ability of streptothricin and analogues to treat XDR Acinetobacter infection
in a murine thigh infection model. Experiments will also specifically examine and define 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 R21 proposal is to determine the tractability of the
streptothricin scaffold for further medicinal chemistry exploration and to identify several advanced candidates for
further exploration.

## Key facts

- **NIH application ID:** 9879683
- **Project number:** 5R21AI140212-02
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** JAMES E KIRBY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,169
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879683

## Citation

> US National Institutes of Health, RePORTER application 9879683, Development of Streptothricin Class Antimicrobials as Novel Therapeutics (5R21AI140212-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879683. Licensed CC0.

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