The rise of multidrug-resistant bacterial infections, which cannot be treated by current antibiotics, is a global threat that requires innovative solutions. A Chinese research team has introduced a method for developing novel antibiotics in the journal Angewandte Chemie. These antibiotics are based on protein building blocks with fluorous lipid chains, inspired by the use of lipoproteins by bacteria to combat microbial competitors. The team aims to enhance the antimicrobial properties of lipopeptides by replacing hydrogen atoms in the lipid chain with fluorine atoms, making them simultaneously water-repellant and fat-repellant.
The researchers synthesized a variety of fluorous lipopeptides and tested their effectiveness against methicillin-resistant Staphylococcus aureus (MRSA), a dangerous strain of bacteria resistant to most antibiotics. The most successful compound, R6F, was made up of six arginine units and a lipid chain with carbon and fluorine atoms. To improve biocompatibility, R6F was enclosed in phospholipid nanoparticles. In mouse models, these nanoparticles were highly effective against sepsis and chronic wound infections caused by MRSA, without any toxic side effects. The nanoparticles attacked the bacteria in multiple ways, inhibiting cell wall synthesis, destabilizing the cell membrane, disrupting the respiratory chain and metabolism, and increasing oxidative stress.
These findings provide potential for the development of potent fluorous peptide drugs to combat multidrug-resistant bacteria. Antibiotic resistance is exacerbated by the widespread misuse and overuse of antibiotics in many countries, including in factory farming where they are given prophylactically to prevent infections and enhance performance. Resistance is evolving against even reserve antibiotics, highlighting the urgent need for new treatment options. Learning from bacteria’s natural defense mechanisms, the research team focused on lipoproteins with positive charges and amphiphilic structures that allow them to bind to and disrupt bacterial membranes.
By utilizing fluorine atoms in lipid chains to enhance membrane binding and disruption, the team created a library of fluorous lipopeptides and identified R6F as a promising candidate for combating MRSA infections. The nanoparticles containing R6F demonstrated impressive efficacy in mouse models, targeting bacteria through multiple mechanisms and avoiding the development of resistance. This innovative approach offers a potential solution to the growing threat of multidrug-resistant bacterial infections and paves the way for the development of effective new antibiotics.
