Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

Abstract

Conspectus The rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance. Peptide natural products stand as promising candidates to meet this need as bacterial resistance is typically slow in response to their unique modes of action. They also have additional benefits including favorable modulation of host immune responses and often possess broad-spectrum activity against notoriously treatment resistant bacterial biofilms. Moreover, nature has provided a wealth of peptide-based natural products from a range of sources, including bacteria and fungi, which can be hijacked in order to combat more dangerous clinically relevant infections. This Account highlights recent advances in the total synthesis and development of a range of peptide-based natural product antibiotics and details the medicinal chemistry approaches used to optimize their activity. In the context of antibiotics with potential to treat Gram-positive bacterial infections, this Account covers the synthesis and optimization of the natural products daptomycin, glycocin F, and alamethicin. In particular, the reported synthesis of daptomycin highlights the utility of on-resin ozonolysis for accessing a key kynurenine residue from the canonical amino acid tryptophan. Furthermore, the investigation into glycocin F analogues uncovered a potent lead compound against Lactobacillus plantarum that bears a non-native thioacetal linkage to a N-acetyl-d-glucosamine (GlcNAc) sugar, which is otherwise O-linked in its native form. For mycobacterial infections, this Account covers the synthesis and optimization of teixobactin, callyaerin A, lassomycin, and trichoderin A. The synthesis of callyaerin A, in particular, highlighted the importance of a (Z)-2,3-diaminoacrylamide motif for antimicrobial activity against Mycobacterium tuberculosis, while the synthesis of trichoderin A highlighted the importance of (R)-stereoconfiguration in a key 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue. Lastly, this Account covers lipopeptide antibiotics bearing activity toward Gram-negative bacterial infections, namely, battacin and paenipeptin C. In both cases, optimization of the N-terminal lipid tails led to the identification of analogues with potent activity toward Escherichia coli and Pseudomonas aeruginosa.

Total Synthesis of Novel Antimicrobial β-Hairpin Capitellacin Via Rapid Flow-Based SPPS Assembly and Regioselective On-Resin Disulfide Cyclisation

“…AMPs are the host defence molecules of living organisms, found in all walks of life, and continue to emerge as promising clinical candidates (Kosikowska and Lesner 2016;Magana et al 2020;Mahlapuu et al 2016;Nijnik and Hancock 2009). AMPs are often broad-spectrum antibiotics with high potency towards a range of pathogens including multi-drug resistant (MDR) Gram-positive and Gram-negative bacteria (Hanna et al 2021). To date, a small number of AMPs have been successfully employed clinically (e.g.…”

Chemische Synthese und Semisynthese von lipidierten Proteinen

“…Lipidierte Peptide kçnnen durch SPPS entweder durch die Kupplung von lipidierten Aminosäuren an die wachsende Peptidkette oder durch die selektive Lipidierung von spezi-fischen ungeschützten Aminosäuren generiert werden. [69] Rekombinante Expressionsmethoden zur Proteingewinnung nutzen routinemäßig E. coli. [70,71] Zusätzlich zu der einfachen genetischen Manipulation und Handhabung wächst E. coli schnell und stellt typischerweise große Mengen an Zielprotein her.A llerdings ist es schwierig,m anche komplexen Säugetierproteine,die einen hohen Grad an struktureller Komplexitäta ufweisen, durch ein einfaches bakterielles Expressionssystem zu erhalten.…”

Chemical Synthesis and Semisynthesis of Lipidated Proteins

“…These issues are mitigated on a solid support as reactions can be driven to completion with excess reagents, which can be removed by simple filtration. Lipopeptides can be accessed by SPPS either by coupling pre‐lipidated amino acids to a growing chain, or by selectively lipidating specific unprotected amino acids following complete elongation of the chain [69] . The production of full‐length lipid‐modified proteins is considerably more challenging; this is due to the inherent size limits of peptides that can be assembled by standard SPPS methods (typically 40–50 residues).…”

“…Lipopeptides can be accessed by SPPS either by coupling pre‐lipidated amino acids to a growing chain, or by selectively lipidating specific unprotected amino acids following complete elongation of the chain. [69] The production of full‐length lipid‐modified proteins is considerably more challenging; this is due to the inherent size limits of peptides that can be assembled by standard SPPS methods (typically 40–50 residues). For these reasons, lipidated peptides and proteins of more than 50 amino acids in length are more commonly accessed by peptide ligation chemistry, in which a peptide and lipopeptide fragment can be chemoselectively fused to access larger targets (Figure 2 ).…”