Microorganisms use amino acid building blocks to produce a wide-range of secondary metabolites with promising antibacterial activity. These can be generated either ribosomally, such as the bacteriocins and lantibiotics, or by non-ribosomal peptide synthases which utilise a wide range of non-proteinogenic amino acids. Structure is often further diversified by cyclisation and/or addition of other moieties after synthesis of the peptide structure.
Bacteriocins are ribosomally-synthesised antimicrobials produced by bacteria to inhibit the growth of other bacteria. Although many are pore-forming cationic peptides, they are structurally and functionally diverse. Some recognise discrete proteinaceous targets and may have intracellular targets as well as acting on the bacterial envelope. While traditionally bacteriocins are regarded as narrow spectrum antibiotics, some show the potential for broad spectrum including activity against Gram-negative pathogens.
Lantibiotics are a special class of bacteriocins which are highly post-translationally modified and often contain multiple ring structures. They are cyclised via the 'dimeric' amino acids lanthionine or methyl-lanthionine. Whilst all contain (methyl)lanthionine moieties, lantibiotic amino acid sequences are highly variable, leading to quite different tertiary structures and biological activities.
The type A lantibiotics have a rod shaped structure and their antibacterial activity is mediated by formation of pores in the bacterial membrane. Type B lantibiotics have a higher degree of cyclisation and inhibit cell wall biosynthesis by binding lipid II. Lipid II is a cell-wall biosynthetic intermediate and a privileged target for antimicrobial agents. As it is not proteinaceous in nature resistant variants cannot arise by simple mutation.
As the name implies rather than being sequenced on the ribosome, non-ribosomal peptides are synthesised by large multifunctional non-ribosomal peptide synthases (NRPS) by a thioether templated mechanism. As these enzymes can incorporate non-proteinogenic amino acids of either stereochemistry their diversity is enormous with many examples already amongst commercial antibiotics (eg daptomycin, vancomycin, bacitracin and polymyxin).