# Fusidic acid derivatization to enhance entry into Gram-negative pathogens

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $209,030

## Abstract

Carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa 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. Fusidic acid is a
steroid antibiotic that has activity against S. aureus inclusive of methicillin-resistant strains, M. tuberculosis,
and N. gonorrhoeae. It also has an excellent safety profile in humans and can be given by both by oral and
intravenous routes. However, it does not penetrate the outer membrane of Gram-negative ESKAPE pathogens,
and, therefore, these pathogens are resistant to achievable drug levels. However, experiments performed in
combination with colistin and other membrane-permeabilizing agents indicate that even the most highly
resistant carbapenemase-producing, colistin-resistant Enterobacteriaceae (expressing NDM-1, KPC, VIM,
and/or MCR-1) and also A. baumannii and P. aeruginosa are susceptible to this antibiotic, if outer membrane
penetration is facilitated. Further, the major circulating resistance elements in S. aureus that bind to and block
the fusidic acid target (EF-Tu) are ineffective against Gram-negative pathogens. Further, target modification-
based resistance confers a significant fitness cost. Therefore, pre-existing resistance in Gram-negatives is
predicted to be negligible, and non-transferable from Gram-positive organisms. Recently so-called eNTRy
rules have defined molecular properties that enhance penetrance into Gram-negatives. Based on intrinsically
compelling properties of fusidic acid, we propose to use novel retrosynthetic semi-synthesis approaches to
apply eNTRy rules during development of fusidic acid analogues, via amine and fluorine substitution. The
underlying goal will be to identify analogues that have broad-spectrum activity against both Gram-positive and
Gram-negative pathogens and fill a critical medical need. There are no previously published efforts along these
lines, and, therefore, the proposed work is both novel and innovative. Importantly, the analogues will be
profiled in a series of complementary functional studies. These will include both in vitro and in vivo
measurements that will distinguish effects of penetrance and activity; activity spectrum studies; and
assessment of metabolic stability; resistance propensity, and toxicology that will help rank compounds for
further intensive exploration. The near-term goal of this two-year, exploratory R21 proposal is to address
potential of retrosynthetic application of eNTRy rules to identify tractable, potent, broad-spectrum fusidic acid
analogues worthy of further exploration.

## Key facts

- **NIH application ID:** 9929528
- **Project number:** 5R21AI146485-02
- **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:** $209,030
- **Award type:** 5
- **Project period:** 2019-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929528

## Citation

> US National Institutes of Health, RePORTER application 9929528, Fusidic acid derivatization to enhance entry into Gram-negative pathogens (5R21AI146485-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9929528. Licensed CC0.

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