Synthetic studies with the brevicidine and laterocidine lipopeptide antibiotics including analogues with enhanced properties and in vivo efficacy

Abstract

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models.

Fig. 1. Structures of brevicidine (1) and laterocidine (2).

Scheme 1. Total SPPS of brevicidine (1). CT = 2-chlorotrityl resin.

Scheme 2. Total SPPS of laterocidine (2). RA = Rink amide resin.

Fig. 2. Overlaid portions of ¹H-NMR spectra obtained for synthetic lipopeptides (blue traces) and previously published spectra (red traces) corresponding to: (A) brevicidine (1) and (B) laterocidine (2). The peak at ca. 3.96 ppm in the published spectrum of brevicidine is attributed to an impurity not present in the synthetic material. Spectra recorded in DMSO-d₆ at RT. Full ¹H-NMR spectra provided in the ESI.

Fig. 3. Brevicidine and laterocidine analogues containing modified macrocycles. Non-ring amino acids shown as one-letter codes. d-Amino acids labelled d.

Scheme 3. Total SPPS of Dap9-Brev (5) and MeDap9-Brev (7).

Scheme 4. Total SPPS of Dap9-Lat (6) and MeDap9-Lat (8).

Fig. 4. In vivo efficacy study. Scattergram of mouse thigh burdens (cfu g⁻¹) following infection with E. coli ATCC 25922 and treatment with test articles, as indicated on the x-axis. The geometric mean burden of each treatment is indicated by the horizontal bar. LOD = limit of detection.