Chemical Synthesis and Structure-Activity Relationship Study Yield Desotamide a Analogues with Improved Antibacterial Activity

Abstract

Desotamides A, a cyclohexapeptide produced by the deep-sea-derived Streptomyces scopuliridis SCSIO ZJ46, displays notable antibacterial activities against strains of Streptococcus pnuemoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus epidermidis (MRSE). In this study, to further explore its antibacterial potential and reveal the antibacterial structure-activity relationship of desotamides, 13 cyclopeptides including 10 new synthetic desotamide A analogues and wollamides B/B1/B2 were synthesized and evaluated for their antibacterial activities against a panel of Gram-positive and -negative pathogens. The bioactivity data reveal that residues at position II and VI greatly impact antibacterial activity. The most potent antibacterial analogues are desotamide A4 (13) and A6 (15) where l-allo-Ile at position II was substituted with l-Ile and Gly at position VI was simultaneously replaced by d-Lys or d-Arg; desotamides A4 (13) and A6 (15) showed a 2-4-fold increase of antibacterial activities against a series of Gram-positive pathogens including the prevalent clinical drug-resistant pathogen methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 8-32 μg/mL compared to the original desotamide A. The enhanced antibacterial activity, broad antibacterial spectrum of desotamides A4 and A6 highlighted their potential as new antibiotic leads for further development.

Keywords: antibacterial; cyclohexapeptides; desotamides; drug-resistant bacteria; solid-phase peptide synthesis; structure-activity relationship.

Figure 1

Chemical structures for natural products desotamides (1–5), wolloamides (6–7) and their synthesized analogues (8–19).

Scheme 1

Synthesis of desotamide A1 on 2-chlorotrityl chloride (2-CTC) resin. Reagents and conditions: (a) Fmoc-l-Asn(trt)-OH, HBTU, DIEA, DMF, 1.5 h; (b) 20% piperidine in DMF, 0.25 h; (c) Fmoc-l-allo-Ile-OH, HBTU, DIEA, DMF, 0.5 h; (d) Fmoc-d-Leu-OH, HBTU, DIEA, DMF, 0.5 h; (e) Fmoc-l-Leu-OH, HBTU, DIEA, DMF, 0.5 h; (f) Fmoc-l-Trp(Boc)-OH, HBTU, DIEA, DMF, 0.5 h; (g) Fmoc-d-Arg(Pbf)-OH, HBTU, DIEA, DMF, 0.5 h; (h) TFA/thioanisole/phenol/dithioglycol/H₂O 33/2/2/1/2, 2 h; (i) HBTU, DIEA, pH 8.0–9.0.

Figure 2

Summary of antibacterial properties and key amino acids for an improved activity for desotamide analogues.

Figure 3

Summary of antibacterial properties and key amino acids for an improved activity for wollamide analogues.