The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae.
Ca(2+)-dependent cyclic lipodepsipeptides are an emerging class of antibiotics for the treatment of infections caused by Gram-positive pathogens. These compounds are synthesized by nonribosomal peptide synthetase (NRPS) complexes encoded by large gene clusters. The gene cluster encoding biosynthetic pathway enzymes for the Streptomyces fradiae A54145 NRP was cloned from a cosmid library and characterized. Four NRPS-encoding genes, responsible for subunits of the synthetase, as well as genes for accessory functions such as acylation, methylation and hydroxylation, were identified by sequence analysis in a 127 kb region of DNA that appears to be located subterminally in the bacterial chromosome. Deduced epimerase domain-encoding sequences within the NRPS genes indicated a D: -stereochemistry for Glu, Lys and Asn residues, as observed for positionally analogous residues in two related compounds, daptomycin, and the calcium-dependent antibiotic (CDA) produced by Streptomyces roseosporus and Streptomyces coelicolor, respectively. A comparison of the structure and the biosynthetic gene cluster of A54145 with those of the related peptides showed many similarities. This information may contribute to the design of experiments to address both fundamental and applied questions in lipopeptide biosynthesis, engineering and drug development.
Miao
Vivian
V
Cubist Pharmaceuticals Inc., 65 Hayden Av., Lexington, MA, 02421, USA.
Brost
Renee
R
Chapple
Joanne
J
She
Kevin
K
Gal
Marie-François Coëffet-Le
MF
Baltz
Richard H
RH
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003360:Cosmids; D015723:Gene Library; D008074:Lipoproteins / Q000096:biosynthesis / Q000737:chemistry; D008969:Molecular Sequence Data; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
C065208:A54145; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008074:Lipoproteins; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase; D002118:Calcium