Development of teixobactin analogues containing highly potent hydrophobic and non-proteogenic amino acids against multidrug-resistant bacteria and biofilms Summary Teixobactin is a cyclic undecadapsipeptide that has demonstrated excellent potency against multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In this article, we present the design, synthesis, and antibacterial evaluations of 16 different teixobactin analogues. These simplified analogues contain commercially available hydrophobic non-proteogenic amino acid residues instead of expensive and synthetically challenging L-alo-enduracididin amino acid residues at position 10 along with different combinations of arginines at positions 3, 4 and 9. The new analogues of teixobactin showed potent antibacterial activity against a broad panel of Gram-positive bacteria, including MRSA and VRE strains. Our work also presents the first demonstration of the potent antibiofilm activity of teixobactin analogs against Staphylococcus species associated with severe chronic infections. Our results suggest that the use of non-proteogenic hydrophobic amino acids at position 10 in combination with arginine at positions 3, 4 and 9 is the key to synthesizing a new generation of highly potent teixobactin analogues to combat resistant bacterial infections and biofilms. |
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Liverpool University
Study demonstrates the potency of a synthetic antibiotic against serious chronic infections
A new synthetic antibiotic developed by researchers at the University of Liverpool is more effective than established drugs against "superbugs" such as MRSA, a new study shows.
The study demonstrates the potent activity of the antibiotic teixobactin against bacterial biofilms. Biofilms are groups of bacteria attached to a surface and/or to each other, which are associated with serious chronic infections in humans.
Almost five million people lose their lives due to infections associated with antibiotic resistance and millions more live with poor quality of life due to treatment failures. Antimicrobial resistance (AMR) is increasing and a review of AMR commissioned by the UK government has predicted that by 2050 a further 10 million people will succumb to drug-resistant infections each year. The development of new antibiotics that can be used as a last resort when other drugs are ineffective is a crucial area of study for healthcare researchers around the world.
This work is based on pioneering research by the University’s Dr Ishwar Singh, an expert in antimicrobial drug discovery and development and medicinal chemistry. A team of researchers led by Dr Singh developed simplified synthetic versions of the natural molecule teixobactin, which producing bacteria use to kill other bacteria in the soil.
They have tested a unique library of synthetic versions of the "breakthrough" antibiotic, optimizing key features of the drug to improve its efficacy and safety, as well as enabling its economical production at scale.
For this latest study, the researchers designed and synthesized very potent teixobactin analogues , but changed the key building block L-allo-enduracididin to commercially available low-cost simplified building blocks such as non-proteogenic amino acids. As a result, analogues are now effective against a wide range of resistant bacterial pathogens, including bacterial isolates from patients and bacterial biofilms.
This is another important step in adapting the natural teixobactin molecule to make it suitable for human use.
Dr Ishwar Singh said: “Teixobactin molecules have the potential to provide new treatment options against multidrug-resistant bacterial infections and biofilms to improve and save lives around the world. “Our study provides a promising foundation for future research and opens avenues to explore the application of teixobactin in various health-related biofilm contexts, including surgical site infections, implant-related surgeries, and patients with cystic fibrosis.”
This work is funded by Innovate UK, the Department of Health and Social Care and the Rosetrees Trust. In addition to the Liverpool University team, researchers from the Singapore Eye Research Institute, Nanyang Technological University (Singapore), Ghent University (Belgium), Utrecht University (Netherlands) and Lincoln University ( United Kingdom).
