A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

Alexey S Vasilchenko; William T Julian; Olda A Lapchinskaya; Genrikh S Katrukha; Vera S Sadykova; Eugene A Rogozhin

doi:10.3389/fmicb.2020.556063

A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

Front Microbiol. 2020 Sep 15:11:556063. doi: 10.3389/fmicb.2020.556063. eCollection 2020.

Authors

Alexey S Vasilchenko¹, William T Julian¹, Olda A Lapchinskaya², Genrikh S Katrukha², Vera S Sadykova², Eugene A Rogozhin^{2

3}

Affiliations

¹ Laboratory of Antimicrobial Resistance, Institute of Environmental and Agricultural Biology (X-BIO), Tyumen State University, Tyumen, Russia.
² Gause Institute of New Antibiotics, Moscow, Russia.
³ Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.

Abstract

In this work, we report the isolation and detailed functional characterization for the new non-ribosomally synthesized antibiotic 5812-A/C, which was derived from metabolites of Streptomyces roseoflavus INA-Ac-5812. According to its chemical structure, the studied 5812-A/C preliminary is composed of a cyclic peptide part covalently bounded with an arabinose residue. N-terminal amino acid sequencing of the native peptide has identified its partial structure of Leu-Asp-Gly-Ser-Gly and consisting of a Tyr residue that is supposed to have a two-component peptide nature for the molecule studied. However, the structural analysis of the antibiotic complex derived from S. roseoflavus INA-Ac-5812 is still ongoing. The mechanism of action of 5812-A/C was assessed in comparison with its most related analog, the lipopeptide antibiotic daptomycin, given the presence in both antimicrobials of an L-kynurenine amino acid residue. The inhibitory activity of 5812-A/C against Gram-positive bacteria including methicillin-resistant strain of Staphylococcus aureus was similar to daptomycin. The mechanism of action of 5812-A/C was associated with the disruption of membrane integrity, which differs in comparison with daptomycin and is most similar to the antimicrobial membrane-disturbing peptides. However, 5812-A/C demonstrated a calcium-dependent mode of action. In addition, unlike daptomycin, 5812-A/C was able to penetrate mature biofilms and inhibit the metabolic activity of embedded S. aureus cells. At the same time, 5812-A/C has no hemolytic activity toward erythrocyte, but possessed weak cytotoxic activity represented by heterochromatin condensation in human buccal epithelium cells. The biological properties of the peptide 5812-A/C suggest its classification as a calcium-dependent antibiotic effective against a wide spectrum of Gram-positive pathogenic bacteria.

Keywords: Streptomyces roseoflavus; anti-biofilm action; calcium-depending antibiotic; daptomycin; lipoglycopeptide antibiotic; peptide antibiotic.