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

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 membranedisturbing 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.

Gausemycins A,B: Cyclic Lipoglycopeptides fromStreptomycessp.**

“…To determine the calcium requirement for antibiotic activity of gausemycins, we measured MICs of gausemycins against a number of strains after addition of 0.45 mM Ca 2+ (Table S19). Despite the fact that a calcium‐dependent mode of action was previously reported for one of the peptide antibiotics isolated from Streptomyces roseoflavus strain INA‐Ac‐5812, [21] we did not observe a Ca 2+ ‐dependence for antibacterial activity of gausemycins. Under the same conditions, daptomycin activity increased at least 10‐fold [41] .…”

Gausemycins A,B: Cyclic Lipoglycopeptides fromStreptomycessp.**

“…43 To determine the calcium requirement for antibiotic activity of gausemycins, we measured MICs of gausemycins against a number of strains after addition of 0.45 mM Ca 2+ (Table S28). Despite the fact that a calcium-dependent mode of action was previously reported for one of the peptide antibiotics isolated from the Streptomyces roseoflavus INA-Ac-5812 strain, 21 we did not observe a Ca 2+ dependence for the antibacterial activity of gausemycin. Under the same conditions, daptomycin activity increased at least 10-fold.…”

“…Thus, the selectivity of gausemycins confirms the presence of specific molecular target(s) in the membranes of susceptible Gram-positive bacteria, and these targets are probably different from those of daptomycin (PG and C55P, C55PP, or lipid II). The death of susceptible cells under gausemycin action can be a result of pore formation and rapid membrane permeabilization, 21 or it can be a result of blockade of some process essential for bacterium survival. Cell wall biosynthesis is one of such processes.…”

Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?

“…Fungal defensin eurocin inhibits cell wall synthesis by binding equimolar to the cell wall precursor lipid II [ 158 ]. Comparison of the mechanisms of action of the two lipopeptides showed that the lipopeptide compound INA-Ac-5812 directly destroys the integrity of the membrane, while daptomycin exhibits an antimicrobial effect, binding to methicillin-resistant Staphylococcus aureus cells and interrupting cell wall biosynthesis with followed by delocalization of peptidoglycan components of the biosynthetic apparatus [ 159 , 160 ]. It has been shown that AMPs are capable of altering DNA morphology, with possible effects of nucleic acid disruption and fragmentation [ 161 ].…”