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Ruthenium-based antibacterial agents with a membrane-disruptive mechanism were designed and synthesized. The complex Ru2 showed excellent antibacterial activity against S. aureus in vitro and in vivo.

The development of new classes of antimicrobial is urgently needed due to the widespread occurrence of multi-resistant pathogens. In this study, three novel ruthenium complexes: [Ru(dmob)2(BTPIP)](PF6)2 (Ru(II)-1), [Ru(dbp)2(BTPIP)](PF6)2 (Ru(II)-2), and [Ru(dpa)2(BTPIP)](PF6)2 (Ru(II)-3) (dpa = 2,2’-dipyridylamine, dmob = 4,4’-dimethoxy-2,2’-bipyridyl, dbp = 4,4’-di- tert-butyl-2,2’-dipyridyl, BTPIP = 4-(benzo[ b]thiophen-2-yl)phenyl-1 H-imidazo[4,5- f][1,10]phenanthroline) are synthesized and investigated as antimicrobial metallodrugs. We demonstrate that all three complexes have significant antimicrobial activity against Staphylococcus aureus by testing their minimal inhibitory concentrations = 0.0015–0.0125 mg/mL. The antibacterial activity of the best active complex Ru(II)-3 is 13 times that of ofloxacin (minimal inhibitory concentration = 19.5 μg/mL). Importantly, Ru(II)-3 not only increases the susceptibility of Staphylococcus aureus to existing common antibiotics but also shows noticeably delayed and decreased resistance in Staphylococcus aureus since the minimal inhibitory concentration values of Ru(II)-3 only increased eightfold times after 20 passages. Furthermore, the biofilms formation and rabbit erythrocyte hemolysis assays verified that Ru(II)-3 also efficiently inhibit the biofilm formation and toxin secretion of Staphylococcus aureus.

The growing burden of antibiotic resistance worldwide calls for developing new classes of antimicrobial strategy. Recently years, the use of adjuvants that rescue antibiotics identified as a promising strategy for overcoming bacterial resistance. In this study, three ruthenium complexes functionalized with furan-substituted ligands([Ru(phen)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-1), [Ru(dmp)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-2) and [Ru(dmb)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-3) (dmb=4,4'-dimethyl-2,2'-bipyridine, phen=1,10-phenanthroline, dmp=2,9-dimethyl-1,10-phenanthroline, CAPIP=(E)-2- (2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline)) were designed and synthesized. The antimicrobial activities of all compounds against S. aureus were assessed by growth inhibition assays. The MIC values of three complexes range from 0.015 to 0.050 mg/ml. Subsequently, the Ru(II)-2 complexes which exhibited strongest antibacterial activity were further tested against bacteria biofilms formation and toxin secretion. In addition, aimed to test whether ruthenium complexes have potential value as antimicrobial adjuvants, the synergism between Ru(Ⅱ)-2 and some antibiotics against S. aureus were examined through checkerboard method. Interestingly, Ru(Ⅱ)-2 could not only effectively inhibit biofilms formation of S. aureus and inhibit the hemolysin toxin secretion, but also selectivity show synergism with two common antibiotics. More importantly, mouse infection study also verified Ru(Ⅱ)-2 were highly effective against S. aureus in vivo.

New effective antimicrobial agents with novel modes of action are urgently needed due to the continued emergence of drug-resistant bacteria. Here, three ruthenium complexes functionalized with benzothiophene: [Ru(phen)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(dmp)2(BTPIP)](ClO4)2 (Ru(II)-2) and [Ru(dmb)2(BTPIP)](ClO4)2 (Ru(II)-3) (dmb = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline) have been synthesized and their antimicrobial activities in vitro were assessed. Minimum inhibitory concentration (MIC) assays indicated that the three Ru(II)-1, Ru(II)-2 and Ru(II)-3 complexes all showed antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. The most active Ru(II)-3 complex was further tested against biofilms. Furthermore, it was also tested whether complex Ru(II)-3 could serve as an antibacterial adjuvant. Interestingly, the checkerboard data showed that Ru(II)-3 selectively exhibited synergism with aminoglycoside antibiotics. More importantly, the observed synergetic effect might be attributed to the inhibition of the regulatory function of SaCcpA. Finally, in vivo bacterial infection treatment studies through a murine skin infection model and skin irritation test were also conducted. All in all, these results confirmed that ruthenium complexes functionalized with benzothiophene have good antimicrobial activity against Staphylococcus aureus.

There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(bpy)2(ETPIP)](ClO4)2 (Ru(II)-2) and [Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-3) (N-N = bpy = 2,2′-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.

The development of ruthenium-based complexes or antimicrobial peptides are identified as a promising strategy for combating drug-resistant bacteria. In this work, four biphenyl-based antibacterial ruthenium complexes by targeting membrane integrity, which act as antimicrobial peptides mimics, were designed and synthesized. In vitro antimicrobial screening demonstrated that four complexes could absolutely inhibit the growth of Staphylococcus aureus (S. aureus) with MIC values ranging from 15.6 to 100 μg/mL. The most active complex Ru(Ⅱ)-1 (MIC = 15.6 μg/mL) could kill S. aureus through targeting the membrane integrity without detectably resistance frequencies. Further investigation including bacteria biofilm formation, hemolysin activity and checkerboard assay were performed as well. The results revealed that Ru(Ⅱ)-1 could inhibit the biofilm formation and α-hemolysis secretion in S. aureus at subinhibitory concentration. More interestingly, the combination use of Ru(Ⅱ)-1 and five traditional antibiotics showing synergistic effect. Finally, based on the mouse model of S. aureus skin infection, Ru(Ⅱ)-1 showed important antibacterial efficacy against S. aureus in vivo, and almost non-toxic against mouse tissue. Our study indicates that introducing membrane targeting ligands onto ruthenium complexes may be an underappreciated strategy for developing antibacterial agents.

It was identified that SarA in S. aureus is a target of Ag+, which further expanded the antibacterial mechanism of Ag+.

Two ruthenium polypyridyl complexes: [Ru(dmb)2(ETPIP)](ClO4)2 (Ru(II)-1) and [Ru(phen)2(ETPIP)](ClO4)2 (Ru(II)-2) (dmb = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, ETPIP = 2-(4-(thiophen-2-ylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), have been synthesized and characterized. Their antimicrobial activities against S. aureus were assessed. Both the complexes Ru(II)-1, and Ru(II)-2 show meaningful activity against Staphylococcus aureus and the lead complex of this set, Ru(II)-2 (MIC = 0.025 mg mL−1), was further tested against biofilms. Given the fact that S. aureus could easily develop resistance to common antimicrobials, we also investigated whether bacteria can easily develop resistance to Ru(II)-2. The result demonstrated that S. aureus did not easily develop resistance to the ruthenium complexes. In addition, the synergism between Ru(II)-2 and common antibiotics against S. aureus was also investigated using the checkerboard method. Interestingly, Ru(II)-2 could increase the susceptibility of S. aureus to the aminoglycoside antibiotic (kanamycin). Finally, a possible mechanism of the observed synergetic effects was investigated by real-time PCR. All in all, these results confirmed that ruthenium complexes have good antimicrobial activity against Staphylococcus aureus.

In this study, flavonoids were extracted using accelerated solvent extraction (ASE) with 80% aqueous methanol. A high-performance liquid chromatography equipped with photodiode array detection and coupled with an electrospray ionization tandem mass spectrometry (HPLC–PDA–ESI/MSn) method has been developed for rapid identification and quantification of flavonoids in the plant extract of Rheum palmatum L. (RPL) seeds from Qinghai. Ten flavonoids from methanolic extract of RPL seeds were screened, of which epicatechin, myricetin, hyperoside, quercitrin and quercetin were identified and quantitatively analyzed for the first time. The absorbance was monitored at 280 nm for epicatechin and 360 nm for other four flavonoids. It was found that the calibration curves for all five analytes showed a good linearity (r2 > 0.999) within the test range and the data of the limit of detection (LOD) and limit of quantification (LOQ) for all investigated compounds were less than 2.98 μg mL−1 based on PDA. The relative standard deviation (R.S.D) values of the intra- and inter-day precisions were 0.98% and 1.65%, respectively. The range of mean recoveries of the five components was 91.3–93.9%, and the R.S.D was 1.3–2.9%. It was also found that the content of quercitrin is the highest in RPL seeds while the contents of epicatechin and myricetin are relatively lower. In addition, the validation procedure confirmed that this method was suitable for providing quality control evaluation of RPL seeds to ensure the therapeutic benefits. Keywords: Seeds of Rheum palmatum L., Identification, Quantification, Flavonoids, Accelerated solvent extraction, HPLC–PDA–ESI/MSn

Retraction of ‘Functional disruption of staphylococcal accessory regulator A from Staphylococcus aureus by silver ions’ by Xiangwen Liao et al., RSC Adv., 2020, 10, 33221–33226. DOI: 10.1039/D0RA06357F.