A naturally inspired antibiotic to target multidrug-resistant pathogens

Area of Science:

• Microbiology
• Drug Discovery
• Genomics

Background:

• Antibiotic resistance in Gram-negative bacteria is a growing global health crisis.
• Colistin is a critical last-resort antibiotic, but resistance is emerging.
• The spread of the mcr-1 gene significantly threatens colistin's efficacy.

Purpose of the Study:

• To investigate naturally occurring colistin congeners for solutions to mcr-1-mediated resistance.
• To identify and synthesize novel compounds effective against colistin-resistant pathogens.
• To develop new therapeutic leads for extensively drug-resistant Gram-negative infections.

Main Methods:

• Bioinformatic analysis of bacterial genomes to identify relevant biosynthetic gene clusters.
• Chemical synthesis of a predicted colistin congener, macolacin.
• In vitro and in vivo testing against Gram-negative pathogens, including those with mcr-1 and intrinsic resistance.
• Evaluation of a macolacin analogue in a mouse infection model.

Main Results:

• A novel colistin congener, macolacin, was identified and synthesized.
• Macolacin demonstrated activity against Gram-negative pathogens expressing mcr-1.
• The compound was effective against intrinsically colistin-resistant bacteria, including Acinetobacter baumannii and Neisseria gonorrhoeae.
• A macolacin analogue showed efficacy in a mouse model against extensively drug-resistant, colistin-resistant Acinetobacter baumannii.

Conclusions:

• Naturally occurring colistin congeners can provide solutions to emerging antibiotic resistance.
• Macolacin represents a promising, naturally inspired therapeutic lead for combating colistin-resistant Gram-negative infections.
• The findings offer a potential strategy to overcome critical threats posed by extensively drug-resistant bacteria.