Saccharomicins, novel heptadecaglycoside antibiotics produced by Saccharothrix espanaensis: antibacterial and mechanistic activities

Abstract

Saccharomicins A and B, two new heptadecaglycoside antibiotics, were isolated from the fermentation broth of the rare actinomycete Saccharothrix espanaensis. They represent a novel class of bactericidal antibiotics that are active both in vitro and in vivo against bacteria and yeast (MICs: Staphylococcus aureus, <0.12 to 0. 5; vancomycin-resistant enterococci, 0.25 to 16; gram-negative bacteria, 0.25 to >128; and yeast, >128 microg/ml), including multiply resistant strains. Saccharomicins protected mice from lethal challenges by staphylococci (subcutaneous 50% effective dose range of 0.06 to 2.6 mg/kg of body weight, depending on the S. aureus strain). The 50% lethal dose by the subcutaneous route was 16 mg/kg. Mechanistic studies with Escherichia coli imp and Bacillus subtilis suggested complete, nonspecific inhibition of DNA, RNA, and protein biosynthesis within 10 min of drug treatment. Microscopic examination of drug-treated cells also suggested cell lysis. These data are consistent with a strong membrane-disruptive activity. The antibacterial activities of the saccharomicins against gram-positive bacteria were unaffected by the presence of Ca(2+) or Mg(2+), but activity against gram-negative bacteria was substantially reduced.

FIG. 1

Structure of saccharomicins A (1) and B (2). Abbreviations: Agl, aglycon; Fuc, fucose; Sac, saccharosamine; Rha, rhamnose; Eva, 4-epi-vancosamine; Dig, digitoxose.

FIG. 2

Kill kinetics of S. aureus Smith.

FIG. 3

Kill kinetics of E. coli imp under stationary (left; cells suspended in saline buffer) and growing (right; cells in minimal medium) conditions. OD, optical density.

FIG. 4

Effects on macromolecular synthesis in an exponential-phase culture of B. subtilis treated with 0.03, 0.06 (MIC), and 0.12 μg of saccharomicin A/ml. Data are percentages of incorporation relative to untreated control for 2 to 14 min of antibiotic treatment and 5 min of pulse-labeling with [³H]TdR, [³H]UdR, and ³H-labeled amino acids (AA).