Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

Abstract

Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an uncultured bacterial source, and demonstrates remarkably high potency against a wide range of resistant pathogens without apparent development of resistance. A rare amino acid residue component of teixobactin, enduracididine, is only known to occur in a small number of natural products that also possess promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin.

Keywords: amino acid; bacterial resistance; enduracididine; natural products; peptide antibiotics.

Figure 1

Structures of the enduracididine family of amino acids (1–6).

Figure 2

Enduracidin A (7) and B (8).

Figure 3

Minosaminomycin (9) and related antibiotic kasugamycin (10).

Figure 4

Enduracididine-containing compound 11 identified in a cytotoxic extract of Leptoclinides dubius [32].

Figure 5

Mannopeptimycins α–ε (12–16).

Figure 6

Regions of the mannopeptimycin structure investigated in structure–activity relationship investigations.

Figure 7

Teixobactin (17).

Scheme 1

Proposed biosynthesis of L-enduracididine (1) and L-β-hydroxyenduracididine (5).

Scheme 2

Synthesis of enduracididine (1) by Shiba et al.

Scheme 3

Synthesis of protected enduracididine diastereomers 31 and 32.

Scheme 4

Synthesis of the C-2 azido diastereomers 36 and 37.

Scheme 5

Synthesis of 2-azido-β-hydroxyenduracididine derivatives 38 and 39.

Scheme 6

Synthesis of protected β-hydroxyenduracididine derivatives 40 and 41.

Scheme 7

Synthesis of C-2 diastereomeric amino acids 46 and 47.

Scheme 8

Synthesis of protected β-hydroxyenduracididines 51 and 52.

Scheme 9

General transformation of alkenes to cyclic sulfonamide 54 via aziridine intermediate 53.

Scheme 10

Synthesis of (±)-enduracididine (1) and (±)-allo-enduracididine (3).

Scheme 11

Synthesis of L-allo-enduracididine (3).

Scheme 12

Synthesis of protected L-allo-enduracididine 63.

Scheme 13

Synthesis of β-hydroxyenduracididine derivative 69.

Scheme 14

Synthesis of minosaminomycin (9).

Scheme 15

Retrosynthetic analysis of mannopeptimycin aglycone (77).

Scheme 16

Synthesis of protected amino acids 87 and 88.

Scheme 17

Synthesis of mannopeptimycin aglycone (77).

Scheme 18

Synthesis of N-mannosylation model guanidine 92 and attempted synthesis of benzyl protected mannosyl D-β-hydroxyenduracididine 94.

Scheme 19

Synthesis of benzyl protected mannosyl D-β-hydroxyenduracididine 97.

Scheme 20

Synthesis of L-β-hydroxyenduracididine 98.

Scheme 21

Total synthesis of mannopeptimycin α (12) and β (13).

Scheme 22

Synthesis of protected L-allo-enduracididine 102.

Scheme 23

The solid phase synthesis of teixobactin (17).

Scheme 24

Retrosynthesis of the macrocyclic core 109 of teixobactin (17).

Scheme 25

Synthesis of macrocycle 117.