Aliphatic /-Amino Acids - /-Lysine, /-Leucine, /-Arginine, and /-Glutamate

Several bacteria (e.g. Clostridium sp.) catabolize L-Lys yielding acetate, butyrate, and ammonia; the first step of this process is the isomerization of L-a-Lys to L-b-Lys [(S)-4] [94]. (S)-b-Lys 4 is frequently found in microorganisms, e.g. as a solubiliz-ing side-chain of aminoglycosides 31-37, e.g. in myomycin B 44 [65] (Scheme 1.5.4), or within the periphery of cyclopeptides (Scheme 1.5.3) encountered in the capreomycins 22 and the tuberactinomycins 23, 24 [95].

Researchers from Takeda have isolated the antibiotics TAN-1057 A-D 29, 30 from Flexibacter sp. [67]. These (S)-b-Lys-derived dipeptides have promising activity against clinically problematic methicillin-resistant strains of Staphylococcus aureus (MRSA). The b-amino acid moiety is essential for the biological activity of TAN-1057 A 29. The bisguanidine 29 seems to have a dual mode of action, involving

TAN-1057 A (29) Scheme 1.5.3. Peptidic natural products related to ß-Lys 4.

h2n oh nh2

streptothricin F (31) ho nh2

albothricin (32)

streptothricin F (31) ho ljho o nh2

albothricin (32)

ljho o myomyein B (n = 1) (34) H2l\L,0 J LL-BM782ct2 (n = 2) (35) T LL-BM782al (n = 3) (36) ° LL-BM782ala (n = 4) (37)

Scheme 1.5.4. Glycopeptide antibiotics related to ß-Lys 4.

nh ho nhch3

lysinomycin (33)

Scheme 1.5.5. Natural products related to ß-Arg 5.

interference with translation and an inhibitory effect on 50S ribosomal subunit formation [67].

Also (R)-b-Lys 4 is found to be a substructure of several antibiotics. Examples are the hydrazinodipeptide negamycin 26 from Streptomyces purpeofuscus, bellenamine 28 from Streptomyces nashvillensis (Actinobacteria), and sperabillins A-D 25 from Pseudomonas fluorescens (Proteobacteria).

Of all the ¿-amino acids, b-Lys 4 seems to be the one most frequently found in bacterial antibiotics. In fact, synthetic analogues of tuberactinomycin and capreo-mycin have been investigated as potential lead structures for new antibacterial drugs at Pfizer [95].

L-b-Arg 5 is a biosynthetic precursor of the antifungal antibiotic blasticidin H 38 that has been obtained, by fermentation, from the bacterium Streptomyces griseo-chromogenes [68] (Scheme 1.5.5).

b-Glu 6, a major constituent of dissolved free amino acids (DFAA) in marine sediments [71], has been detected in red algae (Rhodophyta) [72] and as a potential osmolyte in several marine bacteria, for example obligatory aerobic heterotrophs [70] and methanogenic archaebacteria [8]. N-methyl-b-glutamate has been reported solely as a natural product from the cyanobacterium Prochloron didemni [96].

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