Balhimycin

Sheldrick GM, Paulus E, Vertesy L, Hahn F (1995) Structure of Ureido-Balhimycin. Acta Cryst B51 89... 

Performing mutasynthesis with the balhimycin producer Amycolatopsis balhimycina, several fluorinated glycopeptides finally could be obtained. The muta-synthesis principle was established by Rinehart et al. with the example of neomycin. 2 experimental approach is based on the generation of directed or undirected mutants of a secondary metabolite-producing bacterial strain, which... 

Another important Type 111 PKS is the dihydroxyphenylacetic acid synthase (DHPAS) encoded by the balhimycin gene cluster ia Amycolatopsis mediterraneiP DHPA is the precursor of the nonproteinogenic amino acid 5 -3,5-dihydroxyphenyl-glycine (DHPG), which is found in vancomycin-related antibiotics. DHPAS condenses four malonyl-CoAs to yield an acetate-primed tetraketide, and catalyze the C6-C1 Claisen condensation observed in CHS. 

When the last condensation reaction has occurred, the linear precursor needs to be released from the enzyme. For this important last step, several mechanisms are known simple hydrolysis of the thioester (balhimycin, vancomycin), intramolecular cyclization leading to a lactam (tyrocidine, bacitracin) or a lactone (surfactin), or even reductive thioester cleavage (linear gramicidin). In some cases, the linear precursor is dimerized (gramicidin S) or even trimerized (bacillibactin, enterobactin) before cyclization (Fig. 2). Even though these reactions are critical for the compound s bioactivity, the catalytic domains responsible for the release are not found in all NRPS systems and will therefore be called modifying domains. 

Biaryl structures are wide-spread in many of naturally occuring products including alkaloids, lignans, terpenes, flavonoids, tannins, as well as polyketides, coumarins, peptides, glycopeptides, etc. For example, vancomycin (1) is a basic structure of several related glycopeptide antibiotics [1] balhimycin, actinoidin A, ristocetin A, teicoplanin A2-2, complestatin, etc which are important in medicinal chemistry or as a HPLC chiral stationary phases (vancomycin) [2]. 

Nadkami SR Patel MV, Chatteijee S, Vijaya-kumar EKS, Desikan KR, Blumbach J, Ganguli BN, Limbert M (1994) Balhimycin, a new glycopeptide antibiotic produced by Amycolatopsis sp Y-86,21022 taxonomy, production, isolation and biological-activity. J Antibiot 47 334-341... 

Butz D, Schmiederer T, Hadatsch B, Wohlleben W, Weber T, Suessmuth RD (2008) Module extension of a non-ribosomal peptide synthetase of the glycopeptide antibiotic balhimycin produced by Amyco-latopsis balhimycina. Chembiochem 9 1195 1200... 

Mulyani S, Egel E, Kittel C, Turkanovic S, Wohlleben W, Sussmuth RD, van Pee KH (2010) The thioesterase Bhp is involved in the formation of beta-hydroxytyrosine during balhimycin biosynthesis in Amycolatopsis balhimycina. ChemBioChem 11 266-271... 

This chapter will focus on chiral recognition mechanisms and molecular interactions. The commercialized macrocyclic glycopeptides ristocetin, R, vancomycin, V, teicoplanin, T and its aglycon form, teicoplanin aglycon, TAG will be the main subject of the study since a large database is available in the literature [3-7]. However, non-commercialized avoparcin, balhimycin, and the recently introduced eremomycin macrocyclic glycopeptides [8] are also included in the study for more information on possible mechanisms. 

Macrocycle (trade code) Avoparcin /3 Balhimycin Eremomycin Ristocetin A (R) Teicoplanin A2-2 (7) Teicoplanin aglycon (TAG) Vancomycin (V)... 

Figure 3 shows some similarities between selectors eremomycin, balhimycin, and vancomycin, all three have close structures. It also shows the critical importance of the associated carbohydrate units ristocetin and teicoplanin both share a... 

Abstract Medical studies established that vancomycin and other related macro-cyclic antibiotics have an enhanced antimicrobial activity when they are associated as dimers. The carbohydrate units attached to the vancomycin basket have an essential role in the dimerization reaction. Covalently synthesized dimers were found active against vancomycin-resistant bacterial strains. A great similarity between antibiotic potential and enantioselectivity was established. A covalent vancomycin dimer was studied in capillary electrophoresis producing excellent chiral separation of dansyl amino acids. Balhimycin is a macrocyclic glycopeptide stmcturally similar to vancomycin. The small differences are, however, responsible for drastic differences in enantioselectivity in the same experimental conditions. Contributions from studies examining vancomycin s mechanism for antimicrobial activity have substantially aided our understanding of its mechanism in chiral recognition. 

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