Unraveling the Molecular Mechanism of Selective Antimicrobial Activity of 2(5H)-Furanone Derivative against Staphylococcus aureus

Abstract

Staphylococcus aureus causes various infectious diseases, from skin impetigo to life-threatening bacteremia and sepsis, thus appearing an important target for antimicrobial therapeutics. In turn, the rapid development of antibiotic resistance and biofilm formation makes it extremely robust against treatment. Here, we unravel the molecular mechanism of the antimicrobial activity of the recently unveiled F105 consisting of three pharmacophores: chlorinated 2(5H)-furanone, sulfone, and l-menthol moieties. F105 demonstrates highly selective activity against Gram-positive bacteria and biofilm-embedded S. aureus and exhibits low risk of resistance development. We show explicitly that the fluorescent analogue of F105 rapidly penetrates into Gram-positive bacteria independently of their cell integrity and viability and accumulates there. By contrast, Gram-negative bacteria remain impermeable and, therefore, insusceptible to F105. Apparently, in bacterial cells, F105 induces reactive oxygen species (ROS) formation and nonspecifically interacts with a number of proteins, including ROS-utilizing ones. Using native and 2D PAGE, we confirm that F105 changes the charge of some proteins by either oxidation or direct interaction with them. Therefore, it seems justified to conclude that being simultaneously a ROS inducer and damaging proteins responsible for ROS utilization, F105 impairs the cellular anti-ROS defense representing a prospective ROS-inducing antibacterial agent.

Bidirectional alterations in antibiotics susceptibility in Staphylococcus aureus—Pseudomonas aeruginosa dual-species biofilm

“…This effect could be attributed to either the significant reduction of S. aureus fraction in the biofilm (see Fig. 9, S13, S14) or the repression of the antagonistic factors production by S. aureus due to complex changes in its cell metabolism in the presence of F105 77,78 . Nevertheless, the molecular basis of these complex interbacterial interactions that under certain conditions lead to a clear reversal in the antimicrobials susceptibility requires further investigations.…”

Bidirectional alterations in antibiotics susceptibility in Staphylococcus aureus - Pseudomonas aeruginosa dual-species biofilm

“…Therefore we simulated the S. aureus - P. aeruginosa mixed biofilm formation under the conditions of biofilm-preventing treatment. For that, bacteria were cultivated in the presence of a derivative of 2(5 H )-furanone denoted as F105, identified in recent study as an efficient inhibitor of biofilm formation by S. aureus 73,75 , while exhibiting no significant effect against P. aeruginosa (Table S1). When S. aureus was grown for 48 h in the presence of 2.5 μg/ml of F105, no biofilm was formed and cells growth was retarded, while most of the cells remained viable in both surface-adherent (Fig.…”

“…This effect could be attributed to either the significant reduction of S. aureus fraction in the biofilm (see Fig. 9, S13, S14) or the repression of the antagonistic factors production by S. aureus due to complex changes in its cell metabolism in the presence of F105 73,75 . Nevertheless, the molecular basis of these complex interbacterial interactions that under certain conditions lead to a clear reversal in the antimicrobials susceptibility requires further investigations.…”

“…Derivate of 2(5H)-furanone designed as F105 (3-Chloro-5(S)-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy]-4-[4-methylphenylsulfonyl]-2(5H)-furanone) was described previously 83 and synthesized at the department of Organic Chemistry, A.M. Butlerov Chemical Institute, Kazan Federal University.…”

Spectroscopic and In Vitro Investigations of Boron(III) Complex with Meso-4-Methoxycarbonylpropylsubstituted Dipyrromethene for Fluorescence Bioimaging Applications

“…Fungal cells were stained using [BF 2 L] (2 mg/mL) for 10–30 min. Stained cells were analyzed in vivo using an LSM780 reverse confocal laser scanning microscope (Germany, Jena, Carl Zeiss AG) along a green (488/490–606 nm) channel [ 36 ] (Sharafutdinov et al IJMS, 2019). Microscopy data were processed using ZEN 9.0 software (Carl Zeiss AG).…”