Balhimycin, a new glycopeptide antibiotic produced by Amycolatopsis sp. Y-86,21022. Taxonomy, production, isolation and biological activity.

Nadkarni, S. R.; Patel, Mahesh; Chatterjee, S. K.; Vijayakumar, E. K. S.; Desikan, K. R.; Blumbach, J.; Ganguli, B. N.

doi:10.7164/antibiotics.47.334

Cited by 78 publications

(43 citation statements)

References 4 publications

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“…Balhimycin ( fig. 1 b), a vancomycin-like glycopeptide antibiotic which is synthesized by Amycolatopsis balhimycina (formerly Amycolatopsis mediterranei ) DSM5908 [Nadkarni et al, 1994;Wink et al, 2003], shares the same heptapeptide aglycon as vancomycin ( fig. 1 a), but differs in the glycosylation pattern.…”

Section: Introductionmentioning

confidence: 99%

The Border Sequence of the Balhimycin Biosynthesis Gene Cluster from Amycolatopsis balhimycina Contains bbr, Encoding a StrR-Like Pathway-Specific Regulator

et al. 2007

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Balhimycin, produced by the actinomycete Amycolatopsis balhimycina DSM5908, is a glycopeptide antibiotic highly similar to vancomycin, the antibiotic of ‘last resort’ used for the treatment of resistant Gram-positive pathogenic bacteria. Partial sequence of the balhimycin biosynthesis gene cluster was previously reported. In this work, cosmids which overlap the region of the characterized gene cluster were isolated and sequenced. At the ‘left’ end of the cluster, genes were identified which are involved in balhimycin biosynthesis, transport, resistance and regulation. The ‘right’ end border is defined by a putative 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (dahp) gene. The proximate gene is similar to a type I polyketide synthase gene of the rifamycin producer Amycolatopsis mediterranei indicating that another biosynthesis gene cluster might be located directly next to the balhimycin gene cluster. The newly identified StrR-like pathway-specific regulator, Bbr, was characterized to be a DNA-binding protein and may have a role in balhimycin biosynthesis. Purified N-terminally His-tagged Bbr shows specific DNA-binding to five promoter regions within the gene cluster. By in silico analysis and by comparison of the DNA sequences binding Bbr, conserved inverted repeat sequences for the Bbr-binding site are proposed. The putative Bbr consensus sequence differs from that published for StrR.

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Section: Introductionmentioning

confidence: 99%

The Border Sequence of the Balhimycin Biosynthesis Gene Cluster from Amycolatopsis balhimycina Contains bbr, Encoding a StrR-Like Pathway-Specific Regulator

et al. 2007

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“…Amycolatopsis balhimycina DSM 5908 (formerly described as Amycolatopsis mediterranei) was first isolated from a soil sample originating from the Himalayas (20). It belongs to the order Actinomycetales and synthesizes the glycopeptide antibiotic balhimycin.…”

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confidence: 99%

Self-Resistance and Cell Wall Composition in the Glycopeptide Producer Amycolatopsis balhimycina

Schäberle

Vollmer

Frasch

et al. 2011

Antimicrob Agents Chemother

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Amycolatopsis balhimycina DSM 5908 (formerly described as Amycolatopsis mediterranei) was first isolated from a soil sample originating from the Himalayas (20). It belongs to the order Actinomycetales and synthesizes the glycopeptide antibiotic balhimycin. Balhimycin differs only in its glycosylation pattern from vancomycin, which is used as an antibiotic of last resort against multidrug-resistant Gram-positive bacteria. Since the activities of balhimycin are comparable to those of vancomycin both in vitro and in vivo and A. balhimycina is accessible to genetic manipulation, this strain has become a model organism for analyzing glycopeptide synthesis and resistance (32). Glycopeptide antibiotics inhibit cell wall biosynthesis in Grampositive bacteria by binding the D-alanyl-D-alanine (D-Ala-DAla) terminus of peptidoglycan precursors on the outside surface of the cytoplasmic membrane (24). However, when the usage of vancomycin steadily increased in the 1980s (14), the first vancomycin-resistant enterococci (VRE) were isolated in hospitals (17). In these pathogens, cell wall biosynthesis was reprogrammed in such a way that the pentapeptide of the peptidoglycan precursor terminated in D-alanyl-D-lactate (DAla-D-Lac) rather than D-Ala-D-Ala, thereby causing an ϳ1,000-fold lower binding affinity of the glycopeptide (5). This alteration of the cell wall precursor requires the following three genes: vanH, coding for a dehydrogenase which converts pyruvate to D-Lac (1); vanA, which codes for a D-Ala-D-Lac ligase (4); and vanX, which codes for a DD-dipeptidase that cleaves the D-Ala-D-Ala dipeptide to ensure that only altered peptidoglycan precursors terminating in D-Ala-D-Lac are built up (25). van-like genes which have similarity to the resistance genes from VRE have been found in several glycopeptide producers, such as various Amycolatopsis spp. (16).We report here the rare case of an antibiotic producer carrying a biosynthetic gene cluster without essential resistance genes. The essential vanHAX resistance genes, located elsewhere in the chromosome, are expressed constitutively and are not controlled by the vanRS-like two component system vnlRS, resulting in constitutive production of peptidoglycan precursors terminating in D-Ala-D-Lac. MATERIALS AND METHODSBacterial strains and plasmids. The strains and plasmids used for this study are listed in Table 1.Media and culture conditions. Escherichia coli strains were grown in LB (26) at 37°C. Actinomycetes strains were grown in R5 medium (13) at 30°C. Media were supplemented with antibiotics when necessary to maintain plasmids.DNA preparation and manipulation. The methods used for the isolation and manipulation of DNA for E. coli and actinomycetes were described by Kieser et al. (13). PCR fragments were isolated from agarose gels by use of a QIAquick kit (Qiagen). Restriction endonucleases were obtained from various suppliers and were used according to their specifications.

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“…Balhimycin belongs to the vancomycin class of glycopeptides. It is not approved for medical use yet (11,13).…”

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confidence: 99%

The d -Alanine Residues of Staphylococcus aureus Teichoic Acids Alter the Susceptibility to Vancomycin and the Activity of Autolytic Enzymes

Peschel

Vuong

Otto

et al. 2000

Antimicrob Agents Chemother

224

174

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Recently, Staphylococcus aureus strains with intermediate resistance to vancomycin, the antibiotic of last resort, have been described. Multiple changes in peptidoglycan turnover and structure contribute to the resistance phenotype. Here, we describe that structural changes of teichoic acids in the cell envelope have a considerable influence on the susceptibility to vancomycin and other glycopeptides. S. aureus cells lacking D-alanine esters in teichoic acids exhibited an at least threefold-increased sensitivity to glycopeptide antibiotics. Furthermore, the autolytic activity of the D-alanine mutant was reduced compared to the wild-type, and the mutant was more susceptible to the staphylolytic enzyme lysostaphin. Vancomycin inhibited autolysis at very high concentrations but neither in the wild-type nor in the mutant was the autolytic activity influenced in the range of the MIC. Mutant cells had a considerably higher capacity to bind vancomycin.

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Balhimycin, a new glycopeptide antibiotic produced by Amycolatopsis sp. Y-86,21022. Taxonomy, production, isolation and biological activity.

Cited by 78 publications

References 4 publications

The Border Sequence of the Balhimycin Biosynthesis Gene Cluster from <i>Amycolatopsis balhimycina</i> Contains <i>bbr</i>, Encoding a StrR-Like Pathway-Specific Regulator

The Border Sequence of the Balhimycin Biosynthesis Gene Cluster from <i>Amycolatopsis balhimycina</i> Contains <i>bbr</i>, Encoding a StrR-Like Pathway-Specific Regulator

Self-Resistance and Cell Wall Composition in the Glycopeptide Producer Amycolatopsis balhimycina

The d -Alanine Residues of Staphylococcus aureus Teichoic Acids Alter the Susceptibility to Vancomycin and the Activity of Autolytic Enzymes

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