Anti-bacterial, anti-biofilm and synergistic effects of phenazine-based ruthenium(II) complexes

• Published in: Dalton transactions : an international journal of inorganic chemistry Vol. 53; no. 30; pp. 12627 - 12640
• Main Authors: Martins, Patrícia H R, Romo, Adolfo I B, Gouveia, Jr, Florêncio S, Paz, Iury A, Nascimento, Nilberto R F, Andrade, Alexandre L, Rodríguez-López, Joaquín, de Vasconcelos, Mayron A, Teixeira, Edson Holanda, Moraes, Carlos André Ferreira, Lopes, Luiz G F, Sousa, Eduardo Henrique Silva de
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 30.07.2024
• Subjects: Ampicillin; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Bacteria; Biofilms; Biofilms - drug effects; Biological effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Drug Synergism; Glutathione; Ligands; Metal compounds; Microbial Sensitivity Tests; Nitric oxide; Phenazines - chemistry; Phenazines - pharmacology; Reducing agents; Ruthenium - chemistry; Ruthenium - pharmacology; Ruthenium compounds; Staphylococcus aureus - drug effects; Sulfur trioxide; Synergistic effect
• ISSN: 1477-9226; 1477-9234; 1477-9234
• DOI: 10.1039/d4dt01033g

Antimicrobial resistance has become a global threat to human health, which is coupled with the lack of novel drugs. Metallocompounds have emerged as promising diverse scaffolds for the development of new antibiotics. Herein, we prepared some metal compounds mainly focusing on -[Ru(bpy)(dppz)(SO )(NO)](PF ) (PR02, bpy = 2,2'-bipyridine, dppz = dipyrido[3,2- :2',3'- ]phenazine), in which phenazinic and nitric oxide ligands along with sulfite conferred some key properties. This compound exhibited a redox potential for bound NO of -0.252 V ( Ag|AgCl) and a high pH for nitrosyl-nitro conversion of 9.16, making the nitrosyl ligand the major species. These compounds were still able to bind to DNA structures. Interestingly, reduced glutathione (GSH) was unable to promote significant NO/HNO release, an uncommon feature of many similar systems. However, this reducing agent was essential to generate superoxide radicals. Antimicrobial studies were carried out using six bacterial strains, where none or very low activity was observed for Gram-negative bacteria. However, PR02 and PR ( -[Ru(bpy)(dppz)Cl ]) showed high antibacterial activity in some Gram-positive strains (MBC for up to 4.9 μmol L ), where the activity of PR02 was similar to or at least 4-fold better than that of PR. Besides, PR02 showed capacity to inhibit bacterial biofilm formation, a major health issue leading to bacterial tolerance to antibiotics. Interestingly, we also showed that PR02 can function in synergism with the known antibiotic ampicillin, improving their action up to 4-fold even against resistant strains. Altogether, these results showed that PR02 is a promising antimicrobial nitrosyl ruthenium compound combining features beyond its killing action, which deserves further biological studies.