Engineering ribosomally synthesized and posttranslationally modified peptides as new antibiotics

The rise of antimicrobial resistance is an urgent public health threat demanding the invention of new drugs to combat infections. Naturally sourced nonribosomal peptides (NRPs) have a long history as antimicrobial drugs. Through recent advances in genome mining and engineering technologies, their ribosomally synthesized and posttranslationally modified peptide (RiPP) counterparts are poised to further contribute to the arsenal of anti-infectives. As natural products from diverse organisms involved in interspecies competition, many RiPPs already possess antimicrobial activities that can be further optimized as drug candidates. Owing to the mutability of precursor protein genes that encode their core structures and the availability of diverse posttranslational modification (PTM) enzymes with broad substrate tolerances, RiPP systems are well suited to engineer complex peptides with desired functions.