Combating Antimicrobial Resistance With New-To-Nature Lanthipeptides Created by Genetic Code Expansion

Abstract

Due to the rapid emergence of multi-resistant bacterial strains in recent decades, the commercially available effective antibiotics are becoming increasingly limited. On the other hand, widespread antimicrobial peptides (AMPs) such as the lantibiotic nisin has been used worldwide for more than 40 years without the appearance of significant bacterial resistance. Lantibiotics are ribosomally synthesized antimicrobials generated by posttranslational modifications. Their biotechnological production is of particular interest to redesign natural scaffolds improving their pharmaceutical properties, which has great potential for therapeutic use in human medicine and other areas. However, conventional protein engineering methods are limited to 20 canonical amino acids prescribed by the genetic code. Therefore, the expansion of the genetic code as the most advanced approach in Synthetic Biology allows the addition of new amino acid building blocks (non-canonical amino acids, ncAAs) during protein translation. We now have solid proof-of-principle evidence that bioexpression with these novel building blocks enabled lantibiotics with chemical properties transcending those produced by natural evolution. The unique scaffolds with novel structural and functional properties are the result of this bioengineering. Here we will critically examine and evaluate the use of the expanded genetic code and its alternatives in lantibiotics research over the last 7 years. We anticipate that Synthetic Biology, using engineered lantibiotics and even more complex scaffolds will be a promising tool to address an urgent problem of antibiotic resistance, especially in a class of multi-drug resistant microbes known as superbugs.