Multidrug-resistant bacterial infections that cannot be treated with current antibiotics are a serious global problem. A team of researchers has created a method for producing new antibiotics to combat these resistant pathogens. The drugs are made from protein building blocks with fluorous lipid chains.
Multidrug-resistant bacterial infections that cannot be treated with current antibiotics are a serious global problem. In the journal Angewandte Chemie, a Chinese research team has introduced a method for producing new antibiotics to combat these resistant pathogens. The drugs are based on
The overuse of antibiotics is a common problem, with many countries distributing them without prescriptions and using them in factory farming. This misuse has led to an increase in antibiotic resistance, even against reserve antibiotics. In order to combat this problem, it is important to develop new and innovative alternatives.
We can look to bacteria for inspiration, as they use lipoproteins – small protein molecules with fatty acid chains – in their fights against other microbes. By studying these natural defense mechanisms, we can work towards creating new ways to combat infections.
The researchers focus on developing lipoproteins with positive charge and amphiphilic structure that have been approved for use as drugs. These lipoproteins can bind to bacterial membranes and penetrate through them to the interior. Yiyun Cheng’s team at East China Normal University is working to enhance this effect by substituting hydrogen atoms in the lipid chain with fluorine atoms. This modification makes the lipid chain both water-repellent (hydrophobic) and fat-repellent (lipophobic), resulting in a significantly lower surface.energy increases their affinity to cell membranes while their hydrophobic nature disrupts the integrity of the membrane.
The group created a range (library) of fluorous lipopeptides from fluorinated hydrocarbons and peptide chains. They used the amino acid cysteine to connect the two components through a disulfide bridge. The team evaluated the molecules by testing their effectiveness against methicillin-resistant Staphylococcus aureus (MRSA), a widely spread, highly dangerous bacteria strain that is resistant to almost all antibiotics. The most potent compound they discovered was “R6F,” a fluorouslipopeptide consisting of six arginine units and a lipid chain comprised of eight carbon and thirteen fluorine atoms. In order to enhance biocompatibility, the R6F was enclosed within phospholipid nanoparticles.
In studies using mouse models, R6F nanoparticles demonstrated high efficacy against sepsis and chronic wound infections caused by MRSA. No harmful side effects were observed. The nanoparticles appear to combat the bacteria through multiple mechanisms: they hinder the production of crucial cell-wall components, leading to collapse of the walls; they also penetrate the cell membrane and destabilize it; disrupt the respiratory chain and metabolism; and elevate oxidative stress.e findings suggest that fluorous peptide drugs can effectively kill bacteria, including MRSA, by disrupting their antioxidant defense system. This combination of effects is lethal to the bacteria without any resistance developing. These discoveries can serve as a foundation for the development of highly efficient fluorous peptide drugs for the treatment of multi-drug resistant bacteria.
