# New Antimicrobials that Act Via Membrane Remodeling for Critical Gram-Negative Pathogens

> **NIH NIH R43** · XIRETSA INC. · 2024 · $299,995

## Abstract

PROJECT SUMMARY
Antimicrobial resistance (AMR) is an existential threat to global human health, causing ~1.3M deaths and ~50M
years of life lost annually. Antibiotics are the cornerstone of modern medicine, and we stand to lose advances in
treating myriad diseases if we lose the arms race with AMR. There is an urgent need for novel antibiotics with
unique chemical structures and differentiated mechanisms of action (MOA). The ability of bacteria to rapidly
mutate and develop resistance necessitates the selection of targets that are not only essential but also the
products of multiple genes. The membrane represents such a target and has been successfully exploited by
host immune systems, antimicrobial peptides (AMPs), AMP-like therapeutics such as polymyxins, and
antiseptics. Membrane-targeting small molecules have certain favorable properties relative to AMPs, such as
simpler manufacturing and the potential for better pharmacokinetics. However, despite the promise, membrane-
targeting small molecules have yet to obtain regulatory approval due to challenges with selectivity for bacteria
and safety in vivo. We have discovered a novel class of membrane-modifying antimicrobials, called Anti-infective
Conjugated Electrolytes (ACEs), that we aim to develop into life-saving treatments for the greatest AMR threats
such as lower respiratory infections caused by K. pneumoniae. ACEs are highly selective for bacteria, rapidly
bactericidal, active in vivo, and have anti-biofilm activity, low cytotoxicity, and no hemolytic properties. Subtleties
of the MOA are still under investigation, but ACEs are not lytic and do not exert their antimicrobial activity through
non-specific membrane permeabilization or depolarization. Instead, ACEs induce membrane remodeling, which
is suspected to cause mislocalization or dysfunction of essential membrane proteins. ACE structure-activity
relationships (SAR) have been elucidated and laid the foundation for our recent partnership with NIH Center for
Combating Antibiotic Resistant Bacteria (CC4CARB). New ACE scaffolds co-designed with CC4CARB serve as
the initial subject matter for this project. We will assess ~40 ACEs synthesized by CC4CARB to elucidate
additional SAR and utilize this information to design an additional ~40 ACE derivatives of promising subfamilies
(Aim 1). From this composite set of ACEs, we will identify promising leads via a gated-tier approach (Aim 2). The
activity of derivatives will first be assessed against a panel of critical gram-negative and gram-positive pathogens.
ACEs with high activity and low cytotoxicity will pass to the second tier of in vitro activity and safety testing. The
highest performing 6-8 ACEs will then be assayed for their bactericidal kinetics and antibiofilm activity against
K. pneumoniae. Additionally, the activity of these derivates will be determined in host-relevant media as well as
a Galleria infection model. 4 ACEs will be selected for assessment of resistance development, effi...

## Key facts

- **NIH application ID:** 11007292
- **Project number:** 1R43AI186753-01
- **Recipient organization:** XIRETSA INC.
- **Principal Investigator:** Alex Sajovic Moreland
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $299,995
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007292

## Citation

> US National Institutes of Health, RePORTER application 11007292, New Antimicrobials that Act Via Membrane Remodeling for Critical Gram-Negative Pathogens (1R43AI186753-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11007292. Licensed CC0.

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