Riccardin C derivatives cause cell leakage in Staphylococcus aureus

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major problem in clinical settings, and because it is resistant to most antimicrobial agents, MRSA infections are difficult to treat. We previously reported that synthetic macrocyclic bis(bibenzyl) derivatives, which were originally discovered in liverworts, had anti-MRSA activity. However, the action mechanism responsible was unclear. In the present study, we elucidated the action mechanism of macrocyclic bis(bibenzyl) RC-112 and its partial structure, IDPO-9 (2-phenoxyphenol). Survival experiments demonstrated that RC-112 had a bactericidal effect on MRSA, whereas IDPO-9 had bacteriostatic effects. IDPO-9-resistant mutants exhibited cross-resistance to triclosan, but not to RC-112. The mutation was identified in the fabI, enoyl-acyl carrier protein reductase gene, a target of triclosan. We have not yet isolated the RC-112-resistant mutant. On the other hand, the addition of RC-112, unlike IDPO-9, caused the inflow of ethidium and propidium into S. aureus cells. RC-112-dependent ethidium outflow was observed in ethidium-loaded S. aureus cells. Transmission electron microscopy also revealed that S. aureus cells treated with RC-112 had intracellular lamellar mesosomal-like structures. Intracellular Na+ and K+ concentrations were significantly changed by the RC-112 treatment. These results indicated that RC-112 increased membrane permeability to ethidium, propidium, Na+, and K+, and also that the action mechanism of IDPO-9 was different from those of the other compounds.

In vitro Activity of Robenidine Analog NCL195 in Combination With Outer Membrane Permeabilizers Against Gram-Negative Bacterial Pathogens and Impact on Systemic Gram-Positive Bacterial Infection in Mice

“…TEM images show membrane morphology changes and the presence of mesosome-like membrane structures in NCL195-treated but not in untreated bacteria. The presence of mesosomes is possibly a consequence of cell membrane perturbation through disruption of the membrane potential, consistent with the effects of other antibiotic treatments reported by other workers (Friedrich et al, 2000;Li et al, 2008;Morita et al, 2015;Gao et al, 2019).…”

Targeted and Intracellular Antibacterial Activity against S. agalactiae of the Chimeric Peptides Based on Pheromone and Cell-Penetrating Peptides

“…The propidium iodide (PI) inflow assay was performed as described previously. 26 Logarithmic-phase S. agalactiae CICC 10465 was collected and diluted to OD 600 at 0.4 and incubated with 10 μg/mL PI. Subsequently, the suspension was treated with L1, L2, L10, L11, and ME at corresponding MIC concentrations against different bacteria.…”

Cytotoxic Activity of Riccardin and Perrottetin Derivatives from the Liverwort Lunularia cruciata

“…Perrottetin F showed anti-influenza PA endonuclease activity . Riccardin C exhibited cytotoxicity for a prostate cancer cell line and anti-MRSA activity. , Riccardins C and F were identified as an LXRa agonist/LXRb antagonist and an LXRa antagonist, respectively . Riccardin D, a demethylated derivative of riccardin G, has shown inhibitory effects on several different types of human cancer cells. − …”