How Nature Morphs Peptide Scaffolds into Antibiotics

Abstract

The conventional notion that peptides are poor candidates for orally available drugs because of protease-sensitive peptide bonds, intrinsic hydrophilicity, and ionic charges contrasts with the diversity of antibiotic natural products with peptide-based frameworks that are synthesized and utilized by Nature. Several of these antibiotics, including penicillin and vancomycin, are employed to treat bacterial infections in humans and have been best-selling therapeutics for decades. Others might provide new platforms for the design of novel therapeutics to combat emerging antibioticresistant bacterial pathogens.

Cysteine S -glycosylation, a new post-translational modification found in glycopeptide bacteriocins

“…Cysteine thiols are precursors for conformationally-constraining post-translational modifications such as disulfide bonds, cyclic thioethers and thiazole heterocycles found in a diverse ensemble of antimicrobial peptides including defensins, lantibiotics and thiopeptide antibiotics [5,6]. The sulfur to a-carbon bridges of subtilosin A [26] and thuricin CD [27] are further testament to the versatility of cysteine thiols as substrates for post-translational modification enzymes.…”

“…Some bacteriocins exhibit unusual post-translational modifications [5,6], for example the C-terminal glycosyl ester linkage in microcin E492m [7], but there are no confirmed reports of bacteriocins with glycosylated sidechains.…”

The determination of tRNALeu recognition nucleotides for Escherichia coli L/F transferase

“…Transfer RNAs (tRNAs), in addition to their prominent role in translation, also participate in alternative functions in many organisms in vivo, including amino acid biosynthesis (Ibba and Soll 2004;Sheppard et al 2008), antibiotic biosynthesis (Nolan and Walsh 2009), cell envelope remodeling (Villet et al 2007;Roy and Ibba 2008;Fonvielle et al 2009;Giannouli et al 2009), and targeted proteolysis (Abramochkin and Shrader 1996;Mogk et al 2007; for review and more details, see Banerjee et al 2010;Francklyn and Minajigi 2010). These alternative functions often utilize aminoacyltRNA (aa-tRNA) as a source of activated amino acids, yet deacyl-tRNAs also have regulatory roles in gene expression during amino acid starvation in both prokaryotes and eukaryotes (Wendrich et al 2002;Zaborske et al 2009).…”

Evolution of cyclic peptide protease inhibitors

“…Considerable effort has focused on reprogramming this natural biosynthetic machinery to generate diverse libraries of structurally complex peptides that can be subsequently selected for a desired biological activity. Although various synthetic and in vitro methods have also been developed to generate large peptide libraries from natural and unnatural amino acids and enrich them using affinity-based methods (e.g., phage and ribosomal display, DNA directed synthesis, and encoded synthetic peptide libraries) (8)(9)(10)(11)(12)(13), to date the synthesis and bacterial selection of cyclic peptides containing unnatural amino acid (UAA) building blocks has remained elusive.…”