Introduction
The escalating threat of antimicrobial resistance (AMR) has emerged as one of the most pressing challenges to global public health in the 21st century. AMR occurs when microorganisms—such as bacteria, viruses, fungi, and parasites—evolve mechanisms that render conventional antimicrobial treatments ineffective. This phenomenon has led to a surge in infections that are increasingly difficult to treat, prolonged illness durations, higher healthcare costs, and increased mortality rates. Among the most notorious examples are methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and fluoroquinolone-resistant Pseudomonas aeruginosa, all of which have demonstrated resistance to multiple classes of antibiotics and are associated with severe clinical outcomes.
The efficacy of traditional antibiotics is waning, primarily because most are designed to target specific bacterial pathways such as cell wall synthesis, protein synthesis, or DNA replication. Over time, pathogens have developed adaptive strategies—including enzymatic degradation of drugs, modification of drug targets, and active efflux of antibiotics—that allow them to survive exposure to these treatments. As a result, there is a growing consensus in the scientific and medical communities on the urgent need to identify and develop novel therapeutic agents that function through alternative and less resistance-prone mechanisms.
Metal complexes have garnered significant attention as promising candidates in the search for such alternatives. Unlike organic antibiotics, metal complexes exhibit a broad spectrum of biological activities due to their ability to engage in redox reactions, generate reactive oxygen species (ROS), and form stable interactions with a variety of biomolecules. These include essential components of microbial cells such as membranes, enzymes, proteins, and nucleic acids. Their multifaceted mechanisms of action make them particularly advantageous, as they can simultaneously target multiple cellular processes within pathogens, thereby reducing the likelihood of resistance development.
Moreover, metal complexes can be structurally tailored through the selection of specific ligands, oxidation states, and coordination geometries to enhance their biological activity, selectivity, and bioavailability. This structural versatility opens up new possibilities for designing metal-based therapeutics with optimized pharmacological profiles. As such, metal complexes represent a novel and innovative frontier in the development of next-generation antimicrobial agents, capable of overcoming the limitations of current antibiotic therapies and contributing meaningfully to the global fight against AMR.
2. Materials and Methods
This review article is based on a comprehensive and systematic survey of the scientific literature concerning the use of metal complexes as antimicrobial, antiviral, and antiparasitic agents. A meticulous literature search was conducted using multiple academic databases including PubMed, ScienceDirect, Scopus, and Google Scholar to gather peer-reviewed journal articles, review papers, and experimental studies published over the past two decades.
The inclusion criteria were based on the following: (1) relevance to the synthesis, structural characterization, and biological evaluation of metal complexes; (2) experimental evidence for their antimicrobial, antiviral, or antiparasitic activity; and (3) studies that included insights into the mechanisms of action or biological interactions of these complexes. Articles that solely focused on theoretical or computational studies without experimental validation were excluded unless they provided novel mechanistic insights.
The retrieved data were categorized according to the biological activity of the complexes—namely antimicrobial, antiviral, and antiparasitic—as well as their metal centers, including but not limited to cobalt (Co), copper (Cu), silver (Ag), palladium (Pd), zinc (Zn), and ruthenium (Ru). Special attention was given to the coordination chemistry, oxidation states, ligand architecture (e.g., Schiff bases, triazoles, thiosemicarbazones), and structural motifs that influence biological activity.
Additionally, the review incorporates data derived from in vitro antimicrobial susceptibility assays, such as MIC (Minimum Inhibitory Concentration) and zone of inhibition tests, as well as in vivo studies assessing pharmacodynamics and toxicity. Several mechanistic studies were also considered, including those involving electron microscopy, DNA-binding assays, enzyme inhibition studies, and ROS generation experiments, which helped elucidate the modes of action.
In order to enhance clarity and comparison, the results were tabulated based on compound class, biological target, observed activity, and proposed mechanism of action. Where appropriate, chemical structures and schematic diagrams were included to support the discussion. This methodology ensures that the review is grounded in current scientific understanding and reflects the most promising developments in the field of metal-based therapeutics.
3. Results and Discussion
3.1 Antimicrobial Activity of Metal Complexes
Silver and palladium complexes have shown remarkable efficacy against Gram-positive and Gram-negative bacteria. Silver ions disrupt membrane integrity and protein function, while palladium complexes enhance antibiotic activity through chelation and reactive species generation.
Table 1: Selected Metal Complexes with Antibacterial Activity
| Metal Complex | Target Pathogens | Mode of Action | Reference |
| Silver sulfadiazine | S. aureus, E. coli | Disrupts membrane, binds thiol groups | [11,12] |
| Pd(II)-tetracycline | Tetracycline-resistant E. coli | Increased intracellular accumulation | [13] |
| Coumarin–metal complexes | Candida, Trichophyton, Aspergillus | Inhibits fungal enzymes | [14] |
3.2 Antiviral Potential of Metal Complexes
Cobalt(III) complexes, particularly the CTC series, show significant inhibitory effects against HSV-1 and HIV-1 by targeting viral proteases and preventing membrane fusion. Their structural flexibility allows interactions with viral proteins rich in histidine and cysteine.
Table 2: Cobalt(III) Complexes with Antiviral Activity
| Compound | Virus Target | Mechanism | Effective Concentration | Reference |
| CTC-96 | HSV-1 | Inhibits viral protease, membrane fusion | 5 µg/mL | [21,23] |
| Doxovi™ (CTC derivative) | HIV-1 | Inhibits Sp1 DNA-binding protein | Not specified | [22] |
3.3 Antiparasitic Activity
Copper and cobalt complexes demonstrate significant activity against T. cruzi, the causative agent of Chagas disease. These compounds induce oxidative damage and inhibit key enzymes in the parasite lifecycle.
Table 3: Antiparasitic Metal Complexes Against T. cruzi
| Complex Type | Mode of Action | Observed Effect | Reference |
| Cu(II)–oxindolimine | ROS generation, DNA damage | High antiparasitic activity | [27] |
| Co(II)–triazole | Enzyme inhibition | Moderate efficacy | [29] |
| Ru(II)–thiosemicarbazone | DNA intercalation | Strong inhibition | [29] |
4. Conclusion
Metal complexes offer a powerful alternative to traditional antimicrobial therapies, particularly in light of escalating resistance. Their multi-faceted mechanisms—ranging from membrane disruption to enzyme inhibition—enable them to target pathogens that evade conventional treatments. Continued exploration into ligand design, pharmacokinetics, and selective targeting will further enhance their therapeutic potential. As the AMR crisis intensifies, metal complexes may prove instrumental in developing next-generation antimicrobial, antiviral, and antiparasitic agents.
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