Teixobactin 17 was isolated using the multichannel device, the isolation chip iChip. The iChip allows a single cell to be delivered to an individual chamber where it can grow. This method gives access to cultures of microbes which were previously unobtainable using traditional techniques.
Teixobactin 17 exhibits bactericidal activity through binding of Lipid II, a precursor of peptidoglycan, and therefore shows great potential as the foundation for discovery of a new generation of antibiotics to overcome the development of antimicrobial resistance. Figure 7: Teixobactin Teixobactin 17 demonstrated potent activity against the resistant Gram-positive bacteria, MRSA and vancomycin-resistant Enterococci VRE , as well as other bacterial species including, Mycobacterium tuberculosis Mtb and Clostridium difficile.
Remarkably, no teixobactin-resistant mutants of Staphylococcus aureus or M. This lack of resistance development may possibly be attributable to the mechanism of action which involves binding to Lipid II, inhibiting one of the membrane-associated steps of peptidoglycan biosynthesis [43,44].
An approximately fold reduction in activity was observed when the enduracididine residue is substituted for L-arginine  and almost complete loss of activity was observed when three of the four D-amino acids of this analogue are substituted for their L-counterparts . Biosynthesis of enduracididine In , a radio-labelling study was carried out to determine the biosynthesis of enduracididine 1 . Arginine 18 and its precursors ornithine and citrulline, were found to be incorporated into enduracididine 1 , but not histidine 19 .
Synthetic investigations Synthesis of enduracididine Although several synthetic approaches to enduracididine and its derivatives have been published, the discovery of teixobactin 17 has reignited interest in the synthesis of this unnatural amino acid.
Synthesis of enduracididine by Shiba et al. The synthesis began with Bamberger cleavage of L-methylhistidine 22 to afford amide Reduction of the double bond and cleavage of the three n-butyryl groups afforded lactam Lactam 24 was opened with base and directly treated with guanylating agent 25 giving tosylguanidine 26 which was unstable upon standing.
Immediate treatment with anhydrous HF gave L-enduracididine 1 as a mixture of diastereomers. Scheme 2: Synthesis of enduracididine 1 by Shiba et al. Jump to Scheme 2 Synthesis of enduracididine and allo-enduracididine by Dodd et al. The 9-phenylfluorenyl PhF protecting group was employed to help prevent undesired copper coordination during the key aziridation step. Scheme 3: Synthesis of protected enduracididine diastereomers 31 and Jump to Scheme 3 The synthesis relied on the stereoselective formation of aziridine Attempted optimisation of the yield and diastereoselectivity afforded no improvement.
The two diastereomers 29 and 30 could then be separated and elaborated to afford enantiopure protected L-enduracididine 31 and L-allo-enduracididine The synthesis hinged on the use of azide 34 as a common intermediate to access both diastereomers.
Azide 34 was easily converted to amino azide 36 via a two-step sequence, but conversion of azide 34 to amino azide 37 was more complex and required additional transformations . Scheme 4: Synthesis of the C-2 azido diastereomers 36 and Cleavage of the protecting group allowed installation of the guanidine group using isothiourea 33 before cyclisation was effected using Mitsunobu conditions.
After a six-step conversion of alkene 44 to nosyl intermediate 42, the synthesis diverged to access both C-2 diastereomers. Alternatively, formation of epoxide 45 provided access to diastereomer The C-2 epimer was accessed via Still—Gennari olefination of aldehyde 48 to afford the Z-olefin, which underwent dihydroxylation using potassium osmate to afford diol 50 [61,62].
With both diastereomers in hand, conversion to protected amino acids 46 and 47 was effected in four steps. Scheme 7: Synthesis of C-2 diastereomeric amino acids 46 and The new route proved more efficient than the previous report and provided access to both diastereomers suitably armed with orthogonal protecting groups.
The reaction proceeds with formation of an intermediate aziridine 53 which rearranges upon addition of sodium iodide to afford the desired cyclic sulfonamide Scheme 9: General transformation of alkenes to cyclic sulfonamide 54 via aziridine intermediate Selective deprotection of the sulfonamide Boc group allowed separation of diastereomers 57 and 58 via chromatography which were then converted to Tces 2,2,2-trichloroethoxysulfonyl protected guanidines 59 and Jump to Scheme 10 Synthesis of L-allo-enduracididine by Ling et al.
The synthesis of L-allo-enduracididine 3 was reported to begin with nitro alcohol 61 and afforded the free amino acid in four steps via key intermediate 4-hydroxyarginine The synthesis of nitro alcohol 61 was not described but its preparation has been reported . All four diastereomers were synthesised for comparison with the isolated enduracididine sample. Scheme Synthesis of L-allo-enduracididine 3. Jump to Scheme 11 Synthesis of L-allo-enduracididine by Yuan et al.
The C-4 stereocentre was installed through inversion of the hydroxy group of proline derivative 64 via mesylation and azide displacement to afford Oxidation installed the required carbonyl group which allowed reductive ring opening to afford alcohol Scheme Synthesis of protected L-allo-enduracididine Their synthetic strategy started from silylated serinol 70 to which the mannosyl unit was attached to afford glycosylamine 71, prior to construction of the cyclic guanidine motif and amino acid functionality.
With glycosylamine 71 in hand, attention turned to installation of the guanidine moiety. Silyl deprotection, Swern oxidation and Still—Gennari olefination afforded Z-alkene Diastereoselective dihydroxylation of 73 followed by treatment with 1,1'-thiocarbonyldiimidazole TCDI and sodium azide afforded azide 69 over eight steps in 5.
Journal of the American Chemical Society , 11 , Organic Letters , 17 18 , Marine Drugs , 16 8 , Angewandte Chemie International Edition , 57 12 , Angewandte Chemie , 12 , Total Synthesis and Stereochemical Assignment of Actinoranone. Chemistry - A European Journal , 23 15 , Shinichiro Fuse. Journal of Synthetic Organic Chemistry, Japan , 75 9 , Journal of Synthetic Organic Chemistry, Japan , 75 12 , Timothy A.
Imidazoline scaffold in medicinal chemistry: a patent review — Expert Opinion on Therapeutic Patents , 26 9 , Vivian Ng, Weng C. Chemistry - A European Journal , 22 36 ,Application of these subjects to afford the fully functionalised prison acid 94 was unsuccessful. Chemistry - A Addressee Journal23 15Eternally, no teixobactin-resistant Annual fico report htm of Staphylococcus aureus or M. It was found to present seedling germination of lettuce  and did not expect any amino effect on the creation of protein production in rat hepatoma ploys . The 9-phenylfluorenyl PhF simplistic group was employed to help prevent lethal copper coordination during the key aziridation amino. Scheme Synthesis of L-allo-enduracididine 3. Expansive to Scheme 13 Synthesis of enduracididine-containing biosynthesises Synthesis of Minosaminomycin by Kondo et al.
Muscarine, imidazole, oxazole and thiazole alkaloids. Attempted optimisation of the yield and diastereoselectivity afforded no improvement.
Natural Product Reports , 33 3 , Attempted optimisation of the yield and diastereoselectivity afforded no improvement.
Jump to Figure 2 Enduracidin A 7 and B 8 are depsipeptides with the same composition of seventeen amino acids, sixteen of which make up the cyclic core [11,13,19] and are structurally related to the non-enduracididine containing antibiotic, ramoplanin . Scheme 4: Synthesis of the C-2 azido diastereomers 36 and Teixobactin 17 demonstrated potent activity against the resistant Gram-positive bacteria, MRSA and vancomycin-resistant Enterococci VRE , as well as other bacterial species including, Mycobacterium tuberculosis Mtb and Clostridium difficile. With glycosylamine 71 in hand, attention turned to installation of the guanidine moiety. Experimental procedures and compound characterizations. The C-4 stereocentre was installed through inversion of the hydroxy group of proline derivative 64 via mesylation and azide displacement to afford
The Journal of Organic Chemistry , 82 5 , This was the first time the enduracididine motif had been isolated from a marine source. Scheme 7: Synthesis of C-2 diastereomeric amino acids 46 and
Synthetic investigations Synthesis of enduracididine Although several synthetic approaches to enduracididine and its derivatives have been published, the discovery of teixobactin 17 has reignited interest in the synthesis of this unnatural amino acid. However, encouraged by the successful N-mannosylation of azide 95 to afford adduct 96, Chen et al. It was found to be active against Mycobacteria M.