In vitro antibacterial and time-kill evaluation of phosphanegold(I) dithiocarbamates, R3PAu[S2CN(iPr)CH2CH2OH] for R = Ph, Cy and Et, against a broad range of Gram-positive and Gram-negative bacteria

Abstract

The in vitro antibacterial activity of a series of phosphanegold(I) dithiocarbamates, R 3 PAu[S 2 CN (iPr)CH 2 CH 2 OH] where R = Ph (2), Cy (3) and Et (4), against 25 strains of Gram-positive and Gram-negative bacteria were determined through the disk diffusion method, the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and by time-kill assay. Compounds 2 and 3 have been shown to be specifically active against the tested Gram-positive bacteria, with MIC values ranging from 7.81 to 125 μg/ml. Compound 4 has a broadspectrum activity against 24 strains of Gram-positive and Gram-negative bacteria, with MIC values ranging from 0.98 to 1,000 μg/ml. Noteworthy was that 4, with a very low MIC value of 0.98 μg/ml, is particularly effective against methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus sp., as effective as the standard antibiotic ciprofloxacin. In time-kill studies, the bacteriostatic and bactericidal activities of the tested compounds towards susceptible strains were similar to their characteristics determined by MBC/MIC ratios. In the time-kill assay, 2 and 3 showed only bactericidal activity towards the susceptible strains tested, whereas 4 revealed varying degrees of bactericidal and bacteriostatic activities, results indicating different antibacterial mechanisms are involved.

In vitro antibacterial and time kill evaluation of mononuclear phosphanegold(I) dithiocarbamates

“…While 1 and 2, with hydroxyethyl functionalized dithiocarbamate ligands and 4 are new, 3 is a known compound [35] and the crystal structure of 3 is available [47]. A number of studies are now available suggesting that dithiocarbamate ligands with hydroxyethyl groups possess biological activity [43,44,48,49] and therefore it was thought of interest to extend the studies to 1 and 2, given the anti-bacterial activity of R3PAu[S2CN(iPr)CH2CH2OH] for R = Et, Cy and Ph [42]. Compounds 3 and 4 were included in the present study as they contain Et3P, as in Auranofin®, and have conventional dithiocarbamate ligands which have demonstrated biological activity when complexed to metals [36].…”

“…In keeping in with the wide range of biological activities exhibited by metal (incorporating transition and main group elements) dithiocarbamates [36], a relatively large number of studies have been conducted on phosphanegold(I) dithiocarbamates [37][38][39][40][41], including the determination of biological targets and mechanisms of cell death. Given the emerging interest in the antimicrobial activity of gold compounds [36] and the knowledge that certain metal dithiocarbamates exhibit anti-microbial activity [21], recently a series of phosphanegold(I) dithiocarbamates, namely R3PAu[S2CN(iPr)CH2CH2OH] for R = Et, Cy and Ph, were investigated for antimicrobial activity against a panel of 25 strains of Gram-positive and Gram-negative bacteria [42]. While the R = Et compound had broad range activity against both Gram-positive and Gram-negative bacteria, the R = Cy and Ph compounds exhibited specific activity against Gram-positive bacteria.…”

In VitroEvaluations andIn VivoToxicity and Efficacy Studies of MFM501 against MRSA

“…On the other hand, the rebound effect observed in this study was a common phenomenon in bacterial killing rate studies involving antibacterial agents [19, 20]. This occurrence may due to two distinct bacterial subpopulations with different susceptibility against tested antimicrobial agents in which the selective growth of resistant subpopulation takes over the preferential killing of the susceptible subpopulation at a specified time of interaction [19].…”

“…This occurrence may due to two distinct bacterial subpopulations with different susceptibility against tested antimicrobial agents in which the selective growth of resistant subpopulation takes over the preferential killing of the susceptible subpopulation at a specified time of interaction [19]. …”

1-(2-Hydroxyethyl)imidazolidine-2-thione

“…Such cyclization reactions have been documented in dithiocarbamate chemistry as being a convenient method to form 1-alkyl-2-imidazolidinethiones [8,9], suggesting the organotin reagent is not required for the synthesis. The motivation for the original reaction was to generate bioactive organotin dithiocarbamate compounds inspired by their biological activity, primarily anti-cancer and anti-microbial [10], and as a result of the recent reports of the potential anti-cancer (gold [11], bismuth [12], and zinc [13]) and anti-microbial (copper, silver [14] and gold [15,16]) activities of metal hydroxyethyl-substituted dithiocarbamate compounds, the biological activity of metal dithiocarbamates has been reviewed [17]. Herein, the spectroscopic characterization and X-ray crystal structure determination of 1 are reported.…”