Evaluation of multi-target iridium(iii)-based metallodrugs in combating antimicrobial resistance and infections caused by Staphylococcus aureus.

The rapid emergence and spread of multidrug-resistant bacteria pose a serious challenge to human life and health, necessitating the development of novel antibacterial agents. Herein, to address this challenge, three iridium-based antibacterial agents were prepared and their antimicrobial activity were explored. Importantly, the three complexes all showed robust potency against S. aureus with MIC values in the range of 1.9-7.9 µg mL-1. Notably, the most active complex Ir3 also exhibited relative stability in mammalian fluids and a significant antibacterial effect on clinically isolated drug-resistant bacteria. Mechanism studies further demonstrated that the complex Ir3 can kill S. aureus by disrupting the integrity of the bacterial membrane and inducing ROS production. This multi-target advantage allows Ir3 to not only effectively combat bacterial resistance but also efficiently clear the bacterial biofilm. In addition, when used together, complex Ir3 could enhance the antibacterial potency of some clinical antibiotics against S. aureus. Moreover, both G. mellonella wax worms and mouse infection model demonstrated that Ir3 has low toxicity and robust anti-infective efficacy in vivo. Overall, complex Ir3 can serve as a new antibacterial agent for combating Gram-positive bacterial infections.

Ruthenium polypyridine complexes containing prenyl groups as antibacterial agents against Staphylococcus aureus through a membrane-disruption mechanism.

Four new ruthenium polypyridyl complexes with prenyl groups, [Ru(bpy)2 (MHIP)](PF6 )2 (Ru(II)-1), [Ru(dtb)2 (MHIP)](PF6 )2 (Ru(II)-2), [Ru(dmb)2 (MHIP)](PF6 )2 (Ru(II)-3), and [Ru(dmob)2 (MHIP)](PF6 )2 (Ru(II)-4) (bpy = 2,2'-bipyridine, dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, dmob = 4,4'-dimethoxy-2,2'-bipyridine, and MHIP = 2-(2,6-dimethylhepta-1,5-dien-1-yl)-1H-imidazo[4,f][1,10]phenanthroline), were synthesized and characterized. Their antibacterial activities against Staphylococcus aureus were assessed, and the minimum inhibition concentration (MIC) value of Ru(II)-2 against S. aureus was only 0.5 µg/mL, showing the best antibacterial activity among them. S. aureus could be quickly killed by Ru(II)-2 in 30 min and Ru(II)-2 displayed an obvious inhibitive effect on the formation of a biofilm, which was essential to avoid the development of drug-resistance. Meanwhile, Ru(II)-2 exhibited a stable MIC value against antibiotic-resistant bacteria. The antibacterial mechanism of Ru(II)-2 was probably related to depolarization of the cell membrane, and a change of permeability was associated with the formation of reactive oxygen species, leading to leakage of nucleic acid and bacterial death. Furthermore, Ru(II)-2 hardly showed toxicity to mammalian cells and the Galleria mellonella worm. Finally, murine infection studies also illustrated that Ru(II)-2 was highly effective against S. aureus in vivo.

The synthesis and antibacterial activity study of ruthenium-based metallodrugs with a membrane-disruptive mechanism against Staphylococcus aureus.

The wide spread of drug-resistant bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), poses a tremendous threat to global health. Of particular concern, resistance to vancomycin, linezolid, and daptomycin has already been reported in clinical MRSA strains. New antibacterial agents are urgently needed to overcome this crisis. Here, we designed and synthesized a series of ruthenium-based antibacterial agents via targeting bacterial membrane integrity. Structure-activity relationship studies demonstrated that both the lipophilicity/hydrophilicity ratio and biphenyl group play an important role in elevating the antibacterial activity. To characterize the antibacterial mechanism, we combined scanning electron microscopy, propidium iodide dyeing, and DNA leakage assays. The results demonstrated that Ru2 could destroy the integrity of bacterial cell membranes. In addition, Ru2 can efficiently inhibit biofilm formation and α-hemolysin secretion from Staphylococcus aureus. Finally, in both a mouse skin infection model and a G. mellonella wax worm infection model, Ru2 showed significant antibacterial activity in vivo. Moreover, the Ru2 complex was almost non-toxic. Thus, this work demonstrated that ruthenium-based complexes bearing a biphenyl group are promising agents to combat bacterial infection.

Synthesis of ruthenium polypyridine complexes with benzyloxyl groups and their antibacterial activities against Staphylococcus aureus.

Four new ruthenium polypyridyl complexes, [Ru(bpy)2(BPIP)](PF6)2 (Ru(II)-1), [Ru(dtb)2(BPIP)](PF6)2 (Ru(II)-2), [Ru(dmb)2(BPIP)](PF6)2 (Ru(II)-3) and [Ru(dmob)2(BPIP)](PF6)2 (Ru(II)-4) (bpy = 2,2'-bipyridine, dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, dmob = 4,4'-dimethoxy-2,2'-bipyridine and BPIP = 2-(3,5-bis(benzyloxyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) had been synthesized and characterized. Their antimicrobial activities were investigated against Staphylococcus aureus (S. aureus) and four complexes showed obvious antibacterial effect, especially the minimum inhibition concentration (MIC) value of Ru(II)-3 was only 4 µg/mL. In addition, Ru(II)-3 was able to kill bacteria quickly and inhibit the formation of biofilm. Meanwhile, the cooperative effect between Ru(II)-3 and general antibiotics were tested and the results showed that Ru(II)-3 could enhance the susceptibility of S. aureus to different types of antibiotics. Most importantly, Ru(II)-3 hardly showed cytotoxicity to mammalian erythrocytes both in homelysis experiment and G. mellonella model. After being injected with high doses of the Ru(II)-3in vivo, the G. mellonella worms still exhibited high survival rates. Finally, a mouse skin infection model and G. mellonella infection model was built to determine the antibacterial activity of Ru(II)-3in vivo. The antibacterial mechanism of Ru(II)-3 was probably related to the membrane-disruption. Taken together, ruthenium polypyridine complexes with benzyloxyl groups had the potential to develop an attractive and untraditional antibacterial agent with new mode of action.

Regulation of DNA-binding activity of the Staphylococcus aureus catabolite control protein A by copper (II)-mediated oxidation.

Catabolite control protein A (CcpA) of the human pathogen Staphylococcus aureus is an essential DNA regulator for carbon catabolite repression and virulence, which facilitates bacterial survival and adaptation to a changing environment. Here, we report that copper (II) signaling mediates the DNA-binding capability of CcpA in vitro and in vivo. Copper (II) catalyzes the oxidation of two cysteine residues (Cys216 and Cys242) in CcpA to form intermolecular disulfide bonds between two CcpA dimers, which results in the formation and dissociation of a CcpA tetramer of CcpA from its cognate DNA promoter. We further demonstrate that the two cysteine residues on CcpA are important for S. aureus to resist host innate immunity, indicating that S. aureus CcpA senses the redox-active copper (II) ions as a natural signal to cope with environmental stress. Together, these findings reveal a novel regulatory mechanism for CcpA activity through copper (II)-mediated oxidation.