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Calcarides A-E, antibacterial macrocyclic and linear polyesters from a Calcarisporium strain.

ABSTRACT: Bioactive compounds were detected in crude extracts of the fungus, Calcarisporium sp. KF525, which was isolated from German Wadden Sea water samples. Purification of the metabolites from the extracts yielded the five known polyesters, 15G256?, ?-2, ?, ?-2 and ? (1-5), and five new derivatives thereof, named calcarides A-E (6-10). The chemical structures of the isolated compounds were elucidated on the basis of one- and two-dimensional NMR spectroscopy supported by UV and HRESIMS data. The compounds exhibited inhibitory activities against Staphylococcus epidermidis, Xanthomonas campestris and Propionibacterium acnes. As the antibacterial activities were highly specific with regard to compound and test strain, a tight structure-activity relationship is assumed.

SUBMITTER: Silber J

PROVIDER: S-EPMC3801122 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Calcarides A-E, antibacterial macrocyclic and linear polyesters from a Calcarisporium strain.

Silber Johanna J Ohlendorf Birgit B Labes Antje A Erhard Arlette A Imhoff Johannes F JF

Marine drugs 20130829 9

Bioactive compounds were detected in crude extracts of the fungus, Calcarisporium sp. KF525, which was isolated from German Wadden Sea water samples. Purification of the metabolites from the extracts yielded the five known polyesters, 15G256α, α-2, β, β-2 and π (1-5), and five new derivatives thereof, named calcarides A-E (6-10). The chemical structures of the isolated compounds were elucidated on the basis of one- and two-dimensional NMR spectroscopy supported by UV and HRESIMS data. The compou ...[more]

PMID: 23994907

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Project description:The lack of available treatments for many antimicrobial resistant infections highlights the critical need for antibiotic discovery innovation. Peptides are an underappreciated antibiotic scaffold because they often suffer from proteolytic instability and toxicity towards human cells, making in vivo use challenging. To investigate sequence factors related to serum activity, we adapt an antibacterial display technology to screen a library of peptide macrocycles for antibacterial potential directly in human serum. We identify dozens of new macrocyclic peptide antibiotic sequences and find that serum activity within our library is influenced by peptide length, cationic charge, and the number of disulfide bonds present. Interestingly, an optimized version of our most active lead peptide permeates the outer membrane of gram-negative bacteria without strong inner membrane disruption and kills bacteria slowly while causing cell elongation. This contrasts with traditional cationic antimicrobial peptides, which kill rapidly via lysis of both bacterial membranes. Notably, this optimized variant is not toxic to mammalian cells and retains its function in vivo , suggesting therapeutic promise. Our results support the use of more physiologically relevant conditions when screening peptides for antimicrobial activity which retain in vivo functionality.SignificanceTraditional methods of natural antibiotic discovery are low throughput and cannot keep pace with the development of antimicrobial resistance. Synthetic peptide display technologies offer a high-throughput means of screening drug candidates, but rarely consider functionality beyond simple target binding and do not consider retention of function in vivo . Here, we adapt a function-based, antibacterial display technology to screen a large library of peptide macrocycles directly for bacterial growth inhibition in human serum. This screen identifies an optimized non-toxic macrocyclic peptide antibiotic retaining in vivo function, suggesting this advancement could increase clinical antibiotic discovery efficiency.

Dataset Information

Calcarides A-E, antibacterial macrocyclic and linear polyesters from a Calcarisporium strain.

Publications

Calcarides A-E, antibacterial macrocyclic and linear polyesters from a Calcarisporium strain.

Similar Datasets

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