DUAL APPROACH TO REDUCE TOXICITY IN POLYMYXINS AND REGAIN ACTIVITY AGAINST COLISTIN-RESISTANT STRAINS

Francesc Rabanal; Eudald Asensio; Matilda Bäckberg; Pawel Baranczweski; Y. Cajal; Frederik Deroose; Aghavni Ginosyan; Marc Gros; Maria Isabel Farfan Sellares; K.S. Jensen; Katharina Kloditz; Edgars Liepinsh; Zhuoren Ling; Carina Matias; Aljona Saleh; Carina Vingsbo-Lundberg; Timothy Walsh

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AN APPLICATION OF CLUSTER ANALYSIS WITH THE AFFINITY COEFFICIENT AND EUCLIDEAN DISTANCE TO BACTERIA ANTIMICROBIAL RESISTANCE PROFILE

DUAL APPROACH TO REDUCE TOXICITY IN POLYMYXINS AND REGAIN ACTIVITY AGAINST COLISTIN-RESISTANT STRAINS

Francesc Rabanal

^{*

1},

Eudald Asensio

¹,

Matilda Bäckberg

²,

Pawel Baranczweski

³,

Y. Cajal

¹,

Frederik Deroose

⁴,

Aghavni Ginosyan

³,

Marc Gros

¹,

Maria Isabel Farfan Sellares

¹,

K.S. Jensen

⁵,

Katharina Kloditz

³,

Edgars Liepinsh

⁶,

Zhuoren Ling

⁷,

Carina S. Matias

⁸,

Aljona Saleh

³,

Carina Vingsbo-Lundberg

⁸,

Timothy R. Walsh

⁷

¹ Department of Inorganic and Organic Chemistry, Faculty of Chemistry; Laboratory of Microbiology, Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona and Institute of Nano
² Legado Bioresearch, Stockholm, Sweden
³ Department of Pharmacy, SciLifeLab DDD, Uppsala University, Uppsala, Sweden
⁴ Connecting Pharma BV
⁵ CANDOR Simulations, Denmark
⁶ Latvian Institute of Organic Synthesis, Laboratory of Pharmaceutical Pharmacology, Riga, Latvia
⁷ University of Oxford, Department of Biology, UK
⁸ Statens Serum Institut, Copenhagen, Denmark

Academic Editor: Jordi Vila

Published: 04 May 2026 by MDPI in Antibiotics 2026—Advances in Antimicrobial Action and Resistance session Conventional and Novel Approaches in the Discovery of New Antimicrobial Agents

Abstract:

Antibacterial resistance is rising globally, with particular concern involving multidrug-resistant Gram-negative pathogens listed in the WHO Global Priority List (2024), i. e. carbapenem-resistant and third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae and also carbapenem-resistant Pseudomonas aeruginosa. In this study, we present a dual strategy to reduce polymyxin B and colistin toxicity while maintaining efficacy in the murine model of infection. We used a disulfide-based chemical modification (soft-drug approach) alongside a combination therapy with a clinically approved compound. We will present in vitro microbiological testing (MIC against MDR gram negative bacteria including colistin-resistant strains such as K. pneumoniae ST147), in vivo pharmacokinetic data, acute toxicity and safety evaluation (nephrotoxicity and biomarkers KIM-1, clusterin, NGAL, THF-α) and efficacy in clinically relevant murine infection sepsis models. Taken together, the combination approach increased the tolerated dose of polymyxins by up to fivefold in mice, from 20 to 100 mg/kg subcutaneously and from 4 to 20 mg/kg intravenously, while maintaining antibacterial efficacy.

(https://jpiamr.eu/projects/muryxin/)

Keywords: Polymyxins; therapeutic window; toxicity reduction; in vivo proof-of-concept; carbapenem resistance; third-generation cephalosporin-resistance; colistin-resistance; disulfide soft-drug