Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Urgent need for new antibiotics against Gram-negative pathogens resistant to carbapenems and third-generation cephalosporins.
• Last-resort antibiotics are losing efficacy against these multidrug-resistant (MDR) pathogens.
• ESKAPE pathogens represent a significant global health threat due to antimicrobial resistance.

Purpose of the Study:

• To develop a novel class of synthetic antibiotics targeting carbapenem-resistant Gram-negative bacteria.
• To investigate the mechanism of action of these new chimeric antibiotics.
• To evaluate the efficacy and drug properties of optimized derivatives against MDR pathogens.

Main Methods:

• Design and synthesis of chimeric antibiotics combining β-hairpin peptide macrocycles with polymyxin/colistin natural product scaffolds.
• Assessment of bactericidal activity and mechanism of action, including binding to lipopolysaccharide (LPS) and the β-barrel outer membrane protein BamA.
• In vitro and in vivo evaluation of optimized derivatives against multidrug-resistant Gram-negative pathogens, including ESKAPE pathogens.
• Assessment of colistin resistance and drug properties.

Main Results:

• Developed synthetic chimeric antibiotics with potent bactericidal activity against Gram-negative pathogens.
• Demonstrated a dual mechanism of action involving LPS binding and inhibition of the BamA protein in the β-barrel folding complex.
• Optimized derivatives showed high efficacy against a range of MDR Gram-negative bacteria, including ESKAPE pathogens.
• Overcame existing colistin resistance mechanisms both in vitro and in vivo, with favorable drug properties.

Conclusions:

• The novel class of synthetic antibiotics shows significant potential for treating life-threatening infections caused by MDR Gram-negative pathogens.
• The dual mechanism of action and ability to overcome resistance make these compounds promising candidates for addressing a critical unmet medical need.
• The lead candidate is advancing to preclinical toxicology studies, paving the way for potential clinical trials.