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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.

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.

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.