Antimicrobial Activity of Rhenium Di- and Tricarbonyl Diimine Complexes: Insights on Membrane-Bound S. aureus Protein Binding

Abstract

Antimicrobial resistance is one of the major human health threats, with significant impacts on the global economy. Antibiotics are becoming increasingly ineffective as drug-resistance spreads, imposing an urgent need for new and innovative antimicrobial agents. Metal complexes are an untapped source of antimicrobial potential. Rhenium complexes, amongst others, are particularly attractive due to their low in vivo toxicity and high antimicrobial activity, but little is known about their targets and mechanism of action. In this study, a series of rhenium di- and tricarbonyl diimine complexes were prepared and evaluated for their antimicrobial potential against eight different microorganisms comprising Gram-negative and -positive bacteria. Our data showed that none of the Re dicarbonyl or neutral tricarbonyl species have either bactericidal or bacteriostatic potential. In order to identify possible targets of the molecules, and thus possibly understand the observed differences in the antimicrobial efficacy of the molecules, we computationally evaluated the binding affinity of active and inactive complexes against structurally characterized membrane-bound S. aureus proteins. The computational analysis indicates two possible major targets for this class of compounds, namely lipoteichoic acids flippase (LtaA) and lipoprotein signal peptidase II (LspA). Our results, consistent with the published in vitro studies, will be useful for the future design of rhenium tricarbonyl diimine-based antibiotics.

Computer-Aided Drug Design and Synthesis of Rhenium Clotrimazole Antimicrobial Agents

“…The server also identified the P. aeruginosa MurG as the most suitable template, but provided a slightly different predicted 3D structure of SaMurG with a β-sheet close to the proposed membrane binding interface [ 75 ]. The docking calculations were performed as previously described [ 31 ] with the exception that the receptors were kept rigid. Preliminary molecular docking calculations were carried out with the AutoDock Vina (version 1.2.0) [ 76 ] and the AutoDock4 (version 4.2.6) [ 77 ] softwares.…”

“…Our group [ 31 , 32 , 33 ], and others [ 34 , 35 , 36 , 37 , 38 ], have focused their attention on rhenium-based antibiotic agents [ 39 ]. Wenzel et al first evaluated the antimicrobial potential of rhenium carbonyl complexes, reporting the activity of hetero-tri-organometallic compounds with MIC values of 1.4 µM against Gram-positive bacteria including MRSA [ 40 ].…”

Progress and future of the computational design of antimicrobial peptides (AMPs): bio-inspired functional molecules

“…However, their targets and mechanism of action need further research. [3][4][5] Microbial metabolites are the source of many existing antibiotics and other medicines. For their high diversity and broad bioactivity spectra, short peptides are among the most widely studied secondary metabolites, and the large group of antimicrobial peptides (AMPs) produced by bacteria has been used to treat bacterial, fungal, and viral infections and even cancer.…”

Tricarbonyl rhenium(i) complexes with 8-hydroxyquinolines: structural, chemical, antibacterial, and anticancer characteristics

“…[18][19][20][21][22][23][24][25][26] Several investigations showed the potential anticancer activity of Re(CO) 3 , better than used Pt-drugs, as well as their signicant antimicrobial effects. [27][28][29][30][31][32][33] On the other hand, 8hydroxyquinoline and its derivatives are popular organic compounds used as medicines, e.g., clioquinol (5-chloro-8hydroxy-7-iodoquinoline) exhibits antibacterial and antifungal activity and is used for the treatment of skin infections; nitroxoline (8-hydroxy-5-nitroquinoline) is an antibacterial and anticancer drug; and iodoquinol (5,7-diiodo-8hydroxyquinoline) is effective in the treatment of amebiasis. 34,35 Only 16 crystal structures of tricarbonyl rhenium(I) complexes with 8-hydroxyquinolinato ligands have been reported and structurally characterized in the Cambridge Structural Database (CSD, version 5.45).…”