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

Abstract

<i>Staphylococcus aureus</i> 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 <b>F105</b> consisting of three pharmacophores: chlorinated 2(5<i>H</i>)-furanone, sulfone, and <i>l</i>-menthol moieties. <b>F105</b> demonstrates highly selective activity against Gram-positive bacteria and biofilm-embedded <i>S. aureus</i> and exhibits low risk of resistance development. We show explicitly that the fluorescent analogue of <b>F105</b> 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 <b>F105</b>. Apparently, in bacterial cells, <b>F105</b> 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 <b>F105</b> 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, <b>F105</b> impairs the cellular anti-ROS defense representing a prospective ROS-inducing antibacterial agent.