Antimicrobial Effects of Sulfonyl Derivative of 2(5H)-Furanone against Planktonic and Biofilm Associated Methicillin-Resistant and -Susceptible Staphylococcus aureus

Abstract

The gram-positive opportunistic bacterium <i>Staphylococcus aureus</i> is one of the most common causatives of a variety of diseases including skin and skin structure infection or nosocomial catheter-associated infections. The biofilm formation that is an important virulence factor of this microorganism renders the antibiotic therapy ineffective, because biofilm-embedded bacteria exhibit strongly increased tolerance to antimicrobials. Here, we describe a novel 3-chloro-5(<i>S</i>)-[(1<i>R</i>,2<i>S</i>,5<i>R</i>)-2-isopropyl-5-methylcyclohexyloxy]-4-[4-methylphenylsulfonyl]-2(5<i>H</i>)-furanone (<b>F105</b>), possessing a sulfonyl group and <i>l</i>-menthol moiety. Minimal inhibitory and bactericidal concentration values (MIC and MBC) of <b>F105</b> were 10 and 40 mg/L, respectively, suggesting <b>F105</b> biocidal properties. <b>F105</b> exhibits pronounced activity against biofilm-embedded <i>S. aureus</i> and increases the efficacy of aminoglycosides (amikacin, gentamicin, and kanamycin) and benzalkonium chloride with fractional inhibitory concentration index values of 0.33-0.44 and 0.29, respectively, suggesting an alternative external treatment option, e.g., for wound infections. Moreover, low concentrations (0.5-1.3 mg/L) of <b>F105</b> reduced the MICs of these antimicrobials twofold. By using confocal laser scanning microscopy and CFU counting, we show explicitly that <b>F105</b> also restores the antimicrobial activity of gentamicin and ampicillin against <i>S. aureus</i> biofilms by several orders of magnitude. Biofilm structures were not destroyed but sterilized, with embedded cells being almost completely killed at twofold MBC. While <b>F105</b> is quite toxic (CC₅₀/MBC ratio 0.2), our data suggest that the <b>F105</b> chemotype might be a promising starting point for the development of complex topical agents for combined anti-staphylococcal biofilm-therapies restoring the efficacy of some antibiotics against difficult to treat <i>S. aureus</i> biofilm.