Aryl-alkyl-lysines: Membrane-Active Small Molecules Active against Murine Model of Burn Infection

Area of Science:

• Antimicrobial resistance
• Drug discovery
• Molecular biology

Background:

• Drug-resistant Gram-negative pathogens pose a significant global health threat.
• The emergence of New Delhi metallo-β-lactamase-1 (blaNDM-1) producing strains limits treatment options.

Purpose of the Study:

• To evaluate the efficacy of aryl-alkyl-lysines as potential therapeutics against Gram-negative pathogens.
• To assess the compound's activity against planktonic cells and biofilms.
• To determine the safety and in vivo efficacy of the lead compound.

Main Methods:

• Screening of aryl-alkyl-lysines for antimicrobial activity.
• Assessment of biofilm disruption and planktonic cell killing.
• In vitro resistance selection studies.
• Toxicology studies in Balb/c mice.
• In vivo efficacy testing in a murine model of Acinetobacter baumannii infection.

Main Results:

• Aryl-alkyl-lysines demonstrated potent activity against Gram-negative pathogens.
• One compound effectively killed planktonic cells and dispersed preformed biofilms.
• No resistance was selected in bacteria after multiple passages.
• The compound showed no toxicity in mice up to 17.5 mg/kg.
• Topical application significantly reduced bacterial burden in a murine burn infection model.

Conclusions:

• Aryl-alkyl-lysines represent a promising class of membrane-active agents for treating Gram-negative infections.
• The lead compound exhibits broad-spectrum activity, biofilm disruption capabilities, and a favorable safety profile.
• This discovery offers a potential new strategy to combat challenging multidrug-resistant bacterial infections.