Antimicrobial Agents Based on Metal Complexes: Present Situation and Future Prospects

The rise in antimicrobial resistance is a cause of serious concern since the ages. Therefore, a dire need to explore new antimicrobial entities that can combat against the increasing threat of antibiotic resistance is realized. Studies have shown that the activity of the strongest antibiotics has reduced drastically against many microbes such as microfungi and bacteria (Gram-positive and Gram-negative). A ray of hope, however, was witnessed in early 1940s with the development of new drug discovery and use of metal complexes as antibiotics. Many new metal-based drugs were developed from the metal complexes which are potentially active against a number of ailments such as cancer, malaria, and neurodegenerative diseases. Therefore, this review is an attempt to describe the present scenario and future development of metal complexes as antibiotics against wide array of microbes.


Introduction
Diseases caused by microbial pathogens are the major causes of morbidity and mortality throughout the globe. Each year, more than nine million deaths are attributed to the pathogenic disease worldwide [1]. Developing countries and underdeveloped countries have relatively more afected due to these diseases.
After the discovery of penicillin by Alexander Fleming in 1928, it was thought that humans had declared victory over microbes-based diseases. Since then, thousands of antibiotics have been consumed annually. WHO report on surveillance of antibiotic consumption  states that "Te overall consumption of antibiotics ranged from 4.4 to 64.4 defned daily doses (DDD) per 1000 inhabitants per day." However, just after Fleming's frst use of penicillin for streptococcal meningitis in 1942, penicillin-resistant staphylococci were reported in hospitals and the community. Te emergence of antibiotic resistance in microbes was observed; furthermore, microbes such as bacteria, fungus, bacteria, and parasites showed no response for the medicines, raising serious questions over human triumph over the microbial world. Te antibiotic resistance in microbes not only has posed threat to human health but also for the agriculture and veterinary industries. Traditional antibiotics tend to follow the bullet-target concept, acting on specifc biochemical processes: replication, transcription, translation, and other housekeeping metabolic enzymes, which provide ease of progressive resistance.
Ironically, the rate of development of new antibiotics is lagging behind the rate of emergence of antibiotics resistance; while, cost-efective global access to antibiotics is another challenge for health management systems in underdeveloped countries [2]. Metal and metal-based antimicrobial substances have great potential against antimicrobial resistance pathogens [3]. Metals are reported to target multiple cellular sites such as cellular membrane, genetic material, and reactive oxygen species-mediated cellular pleiotropic efects on microbial cells, contrary to organic antibiotics that act on specifc targets on biochemical pathways such as replication, transcription, translation, and enzymatic reaction. Hence, there is an urgent need for the development of novel, wide spectrum antimicrobial agents that could target and eliminate antibiotics resistance microbes. A renewed interest in metals as antimicrobial and biocidal agents is refected in hopes that less resistance will evolve.

Development of Antibiotics
Metals have been in use for their antimicrobial properties since thousands of years. Te prevalence of Cu and Ag vessels and their use for water disinfection and food preservation since the time of the Persian Empire is well-known [4]. Tere are records of Paracelsus, a Swiss physician, using the silver internally and silver nitrate externally for treatment of wounds in the 1520s, which is followed even today. Similarly, silver sulfadiazine creams (Silvazine and Flamazine) are topical ointments that are used globally for the treatment of wound infections. Silver has also been used variedly in medicine, such as silver sutures for treating vaginal tears caused during the childbirth [5], silver nitrate (AgNO 3 ) for preventing ophthalmia neonatorum [6], and silver foils for preventing surgical wounds from infection [7]. Moreover, compounds like Te, Mg, As oxides, Cu, and Hg salts have been used to cure diseases such as leprosy, tuberculosis, gonorrhoea, and syphilis [8][9][10]. Tis extensive use of metal based cures continued till the discovery of penicillin in 1920s. Now, as the humans are witnessing an ever-escalating threat of multidrug resistance, the use of antimicrobial metals is undergoing a much needed renaissance.

Metal Complex-Based Antimicrobial Compounds
Diferent metal complexes have their respective biological roles, and therefore, their design may help in developing new diagnostic probes as well as medicines. Metal complexes have emerged as great alternatives to organic compounds as they have specifc steric and electronic efects that lead to diferent mechanisms of action (e.g., electron transfer and redox processes) [3]. Metals, because of being less electronegative, tend to promptly form positively charged ions, and this property lends them greater solubility in the biological fuids. Te positively charged ions thus formed have afnity for electron-rich biomolecules, such as DNA and proteins, and play an important role in stabilizing/infuencing their tertiary or quaternary structures. Te current review shall revolve around the antibiotic compounds based on metal complexes.

Silver and Its
Derivatives. Silver and its compounds have been in use as antimicrobial agents since ages. Te antimicrobial properties of silver and its salts have been well researched and discussed [11][12][13][14].
Although silver and its complexes have shown cytotoxic efects against Gram-positive/Gram-negative bacteria and fungi, much is not known about the exact mechanism of action of silver except for its strong afnity to react with thiol (sulfhydryl, SH) groups in the bacterial cell, whether they be in structural or functional (enzymic) proteins. It has been demonstrated that silver induces structural changes in bacterial cells and interacts with nucleic acids [18,19]. Tese interactions result in the denaturation of proteins further causing impairment of the membrane functions [20,21]. Silver ions can produce ROS, which may target lipids, DNA, RNA, and proteins, and cause malfunctioning of membranes, proteins, and the DNA replication machinery [22,23]. Moreover, DNA molecules in bacterial cytoplasm lose their ability to replicate upon treatment with silver leading to death of bacteria [20].
Few newer categories of silver complexes such as Nheterocyclic carbene (NHC) complexes, phosphine complexes, or N-heterocyclic complexes of silver (I) have been found to have antimicrobial properties [24]. Te NHC ligands make stable complexes and silver NHC complexes ( Figure 2) help modulate release of silver for its systemic delivery. Various pincer Ag (I)-carbene complexes have exhibited antimicrobial activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa), probably by intercalating with DNA or by disrupting the cell membrane [25].
Biologically synthesized silver nanoparticles (SNPs) are being widely using in the feld of medicine. Tey have shown tremendous and very strong antibacterial properties against various bacterial species [28]. Savithramma et al. synthesized silver nanoparticles from stem bark extracts of Boswellia and Shorea and leaf extract of Svensonia. Te SNPs synthesized from bark extracts of Boswellia ovalifoliolata and Shorea tumbuggaia showed toxic towards Klebsiella and Aspergillus and Pseudomonas and Fusarium species, respectively. But the AgSNP synthesized from leaf extract of Svensonia hyderobadensis exhibit strong efect against Pseudomonas and Rhizopus species [29].
Sondi and Salopek-Sondi studied that the concentration of Ag NPs plays an essential role to stop the growth of bacteria and the inhibition rate of E. coli is directly proportional to the concentration of Ag NPs. Ag NPs signifcantly damaged and destroyed cells and protein functions of E. coli due to its accumulation [30]. Te antibacterial activity of Ag NPs is size dependent, since the small size Ag NPs (110 nm) have shown high tendency to interact with cell walls of bacteria [31].

Copper and Its Derivatives.
Copper is an essential metal needed by organisms for many functions but can be toxic in large concentration [32]. Tere are many copper-containing proteins present in microbes where copper acts as an electron donor/acceptor due to its ability to switch between copper (II) and copper (I) ions [33]. In order to improve its antimicrobial activity, many researchers studied the coordination of organic molecules with copper. Tere are diferent mechanisms of action that depend on the geometry of the complexes and the nature of the ligand (Figure 3) [34,35]. Although the exact mechanism of the antimicrobial activity of copper is not known, many investigations have shown that reactive oxygen species (RoS) produced through Fenton-type reactions damages DNA. Te release of copper ions causes inactivation of enzymes that leads to its toxicity [36].
Te compound 4, a tetrahedral mixed-ligand copper (I) bromide complex (Figure 4), exhibited 100 times greater activity against Escherichia coli, Xanthomonas campestris, Bacillus subtilis and Bacillus cereus, as compared to ampicillin [37] as it relied on disrupting the bacterial membrane by generating reactive oxygen species (ROS).
Te antibacterial property of copper-based complexes is largely due to the formation of a phthalimide-based copper (II) complex 5 [38]. Te phthalimide moieties and their derivatives are known to possess anticancer [39], antimicrobial [40], anti-infammatory [41], and antimalarial properties [42], and this property stems from their capability to disrupt the DNA.
Sulfonamide ligands coordinated with copper (II) can interfere with the biosynthesis of tetrahydrofolic acid which is essential for bacterial metabolism [33,43]. Studies have also revealed that copper (II) complexes with fve-membered heterocyclic ring substituents (sulfsoxazole 7, sulfamethoxazole, and sulfamethizole) ( Figure 3) have been found to possess greater antimicrobial activity against both Grampositive and Gram-negative bacteria as compared to free sulfonamides [33].
Only the ionic form of free sulfonamides has an active antibacterial activity [44], but for its anionic form, the penetration efciency across the lipoidal bacterial membrane is very low, which is due to its low lipophilicity. To enhance the permeation of the drug inside the cell, one possibility is to increase their lipophilicity by complexation of this kind of ligands with metal ions.
Te antimicrobial activity of the deposited copper and copper oxide flms against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was observed [45]. It was observed that there was 5-log 10 reduction in the viable counts of E. coli on the copper thin flms and 2-log 10 reduction on copper oxide flms after 30 minutes and 1 hour, respectively. But in case of S. aureus, both copper and copper oxide flms exhibited 4-log 10 reduction after 1 hour. Te high antimicrobial efcacy of the Cu 2 O flms, as compared to that of the pure copper flms, suggests that oxide formation on copper objects should not signifcantly impair their antimicrobial activity. Te novel Schif base,     Klebsiella pneumoniae, and Pseudomonas aeruginosa and fungus such as Aspergillus favus, Aspergillus niger, and Candida albicans. Te copper nanoparticles showed more inhibitory activity in bacteria than that in fungus [47]. In the last few decades, there has been signifcant progress in designing of diferent copper-based complexes having varied ligands, substituents, and geometries which exhibited signifcant antimicrobial properties.

Zinc and Its
Derivatives. It is an important element for living organisms as it is involved in many vital cellular reactions [48,49]. Zn 2+ ion plays a key role as metalloenzymes and in metal-based pharmaceuticals [50][51][52] especially as antiseptic [53]. Zinc inhibits the growth of many bacteria, e.g., Escherichia coli, Streptococcus faecalis, and some strains of soil bacteria [54]. Tere are two modes of its action: (i) direct action, whereby, microbial membrane is destabilized and its permeability is increased [55]; (ii) indirect action, whereby, interaction with nucleic acids leads to deactivation of respiratory enzymes [56]. Te Zn (II) complexes have been found to exhibit antifungal activities against Candida albicans and Aspergillus niger which are around 4 and 10 times higher as compared to antifungal activities of fuconazole against them [57]. Most of the metal complexes have been found to exhibit greater activities as compared to the Schif base ligand which are a result of the lipophilic nature of the complexes which eases crossmembrane movement. Te square pyramidal Zn (II) complexes possess bacteriostatic as well as bactericidal properties against a wide array of bacterial and fungal strains [58]. A study was conducted to fnd out antimicrobial potential of Zn (II) complexes, involving ibuprofen with presence of Ndonor heterocyclic ligands and with variable shapes and structures. Te results revealed that antimicrobial activities of the complexes against Gram-positive (Micrococcus luteus, Staphylococcus aureus, and Bacillus subtilis) and Gramnegative (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) were signifcantly infuenced by their geometries ( Figure 5) [59]. Te complexation of cyclam to Zn (II) is another example that shows geometrical and structural importance of metallodrug. Some studies related to complexation of Xylylbicyclam, an anti-HIV drug to diferent types of metal ions, especially Zn 2+ , into the cyclam rings increases its coreceptor (CXCR4) binding strength which is the reason for its anti-HIV activity [60][61][62] (Figure 6, compound 9). Confgurationally restricted analogue of bismacrocyclic cyclam CXCR4 receptor antagonist and its Zn (II) complex has been produced which lead to increased interaction with protein, therefore, resulted results in improvement of its anti-HIV activity [63] (Figure 6, compound 10).

Iron.
Iron ion plays an important role in the growth of pathogenic bacteria; therefore, its coordination compounds with such organic molecules which display antimicrobial activity may be of great importance [64]. In this way, iron could be used as a carrier for the potent antimicrobial molecules, and the metalloantibiotics produced under this strategy would also enhance the efciency of the antimicrobial drugs through efcient delivery. Te ironquinoxaline derivative compounds to cure tuberculosis were developed under this strategy which helped in greatly enhancing the antibacterial activity of quinoxaline derivatives. It was, therefore, concluded that such iron complexes have a signifcantly higher activity against Mycobacterium tuberculosis as compared to the free ligands [65,66]. Te higher activity of these iron complexes is the result of the fact that iron (III) efciently carries the bioactive ligands and tends to increase their concentrations inside the target microbial cells. Similarly, iron (III) complexes of 1,2,4-triazole Schif bases have also been revealed to exhibit greater antimicrobial action against various Gram-positive and Gram-negative bacteria as compared to their free ligands [67]. Te presence of quinolones is the reason for the bioactivity of the complexes as they disrupt enzyme production. Chelation also helps increase the bioactivity of the complex as it enhances the lipophilic character of the central metal atom and helps it pass through the microbial membrane quite easily. Tere is potential of designing bioorganometallic derivatives with higher antimicrobial activity by including either an antimicrobial component, active moiety of the drug or the metal which resembles a part of the drug [68]. Organometallic complex ferroquine has been formed by adding a ferrocenyl moiety into the structure of the antimalarial chloroquine that results in better mode of action as compared to parent drug [69]. Te ferrocene moiety present in the ferroquine turns it efective against even chloroquine-resistant strains as it produces reactive oxygen species that kill the parasites.

Ruthenium and Its
Derivatives. Ruthenium is the second member of group 8 transition metals (atomic number 44) and a potential antimicrobial agent. Te octahedral ruthenium (II) complexes exhibit antimicrobial properties against Mycobacterium smegmatis [70]. While such ruthenium complexes have been reported to inhibit M. smegmatis at MIC of 2 µg/mL, they have no efect on S. aureus (MSSA), P. aeruginosa, E. coli, C. albicans, and C. neoformans. Furthermore, the investigation of the antimicrobial activity of mono-, di-, and oligonuclear inert polypyridyl ruthenium (II) complexes is also deciphered [71]. It has been revealed that the dinuclear Ru (II) complexes linked by long fexible alkane chains (compound 18, Figure 7) exhibit signifcant inhibitory activity against both Gram-positive and Gramnegative bacteria but at the same time are less harming to human cells.
International Journal of Biomaterials 3.6. Gold and Its Derivatives. Gold has been used for the treatment of syphilis, tuberculosis, and infammatory rheumatoid and also has great antimicrobial potential. Gold (I) alkynyl chromone complexes have been reported to have high levels of inhibitory activities against methicillinsensitive (MSSA) and methicillin-resistant (MRSA) S. aureus but failed against E. coli [74]. Auranofn, a goldbased drug for the treatment of arthritis has been reported to inhibit thioredoxin reductase (Trx), an enzyme that helps bacteria in maintaining the thiol-redox balance and protects them against reactive oxidative species. Te drug therefore exhibited signifcant activity against various Gram-positive bacteria including multidrug resistant bacteria as well as M. tuberculosis, but it has been inefective against Gramnegative bacteria as the glutathione system in Gram-negative bacteria compensates for the loss of the reducing ability of Trx [75,76]. In some cases, the outer membranes in Gramnegative bacteria have been found to be efective in avoiding auranofn accumulation [77]. Te gold (I) bis-N-heterocyclic carbene complexes have exhibited notable activity against methicillin-resistantS. aureus (MRSA) strains and acted by disrupting the enzyme thioredoxin reductase (TrxRs) but were less efective when compared to auranofn or standard antibiotics [78]. Figure 5: Structure of zinc-ibuprofen complexes [59].  Also, a small decrease was reported in extracellular protein content of the bacterium [81]. Aluminium oxide (AlNPs) and sulphur nanoparticles (SNPs) nanoparticles synthesized from Colletotrichum sp. have been studied for their inhibitory action against pathogens such as Listeria monocytogenes, Salmonella typhi, Chromobacterium violaceum, Fusarium oxysporum, and Aspergillus favus, and it was found that while SNPs were most efective against Salmonella typhi, the AlNPs were signifcantly successful against F. oxysporum. It was also noted that the activity of several antibiotics also increased when used in combination with these metal-based nanoparticles. Te synthesis and antimicrobial activity of aluminium (III) was reported [82]. Te synthesis of N 2 O 2 tetradentate Schif base ligand from salicylaldehyde and ophenylenediamine and the ligand reacted with Al (III). Tese Al (III) complexes show good antibacterial activity as compared to its ligands. Te antimicrobial activity of the complexes is based on the chelation theory; chelation reduces the polarity of the metal atom because of partial sharing of its positive charge with the donor groups and possible π-electron delocalization within the whole chelate ring. Also, chelation increases the lipophilic nature of the central atom which subsequently favours its permeation through the lipid layer of the cell membrane [83].

Gallium and Its
Derivatives. Ga can be used as an antimicrobial agent alone or can be combined with other materials. Ga can be used in several forms, such as Gaprotoporphyrin or Ga (III) tetra-(4-carboxypenyl) porphyrin (ClGaTCPP), for its antimicrobial activity. It was studied that the iron mimetic metal gallium Gaprotoporphyrin is recognised by the cell as iron, therefore, is metabolized via the same mechanism. Tis inhibits the essential pathways in bacterial cells, disrupts cellular respiration, and induces ROS production. Once Ga is digested, it disrupts vital cellular pathways (prevents electron transfer for ATP production by respiratory pathways, enzymes are inhibited to break down Ga, obstructing nutrient/iron release and promoting starvation, Ga's inability to be reduced such as iron blocks efux pumps) [84]. Generally, this limits cellular respiration through the production of ROS, therefore damaging cell DNA and prompting cell death.

Indium and Its
Derivatives. Te antimicrobial activity of indium tin oxide (ITO) conjugated with T4 bacteriophage against E. coli was reported. It was observed that there was 99.9% reduction in bacterial concentration (E. coli) with bare as well as the amine, carboxylic, and methyl functionalized ITO/T4 surfaces. As anticipated, a single dose of immobilized bacteriophage was sufcient to eliminate further surge of bacterial population. All of the ITO/T4 systems maintained their antimicrobial activity in the presence of model food components. However, the antimicrobial activity was afected by pH; at pH 5, whereby, the bacteria's growth was physiologically inhibited, generally no reduction in E. coli concentration was detected [85].
Te antibacterial activity of indium oxide thin flm which is prepared using thermal evaporation of indium metal in International Journal of Biomaterials vacuum on a glass substrate at 25°C and then subjected to thermal oxidation at temperature 400°C for 1 h was observed. In 2 O 3 exhibited strong antimicrobial efects against Gram-negative bacteria. Te results demonstrate that In 2 O 3 causes damage to the bacterial cell membranes and controls the activity of some membranous enzymes which kills the E. coli and can be useful in the treatment of infectious diseases [86].

Mechanism of Action of Antimicrobial Metal Complexes.
Various metals have been used in the treatment of diferent diseases; metals such as gold drugs, Myocrisin, and Auranofn are used for the treatment of rheumatoid arthritis. Teir mode of actions is also diferent ( Table 1). Silver and its complexes have shown cytotoxic efects against Grampositive/Gram-negative bacteria and fungi, much is not known about the exact mechanism of action of silver except for its strong afnity to react with thiol (sulfhydryl, SH) groups in the bacterial cell, whether they be in structural or functional (enzymic) proteins. It has been demonstrated that silver induces structural changes in bacterial cells and interacts with nucleic acids [18,19]. Tese interactions result in the denaturation of proteins further causing impairment of the membrane functions [20,21]. Silver ions can produce ROS, which may target lipids, DNA, RNA and proteins, and cause malfunctioning of membranes, proteins, and the DNA replication machinery [22,23]. Moreover, DNA molecules in bacterial cytoplasm lose their ability to replicate upon treatment with silver leading to the death of bacteria [20]. Copper has diferent mechanisms of action that depend on the geometry of the complexes and the nature of the ligand (Figure 3) [34,35]. Although the exact mechanism of the antimicrobial activity of copper is not known, many investigations have shown that reactive oxygen species (RoS) produced through Fenton-type reactions damages DNA. Te release of copper ions causes inactivation of enzymes that leads to its toxicity [36]. Zinc has two modes of mechanisms: (i) direct action, whereby, microbial membrane is destabilized, and its permeability is increased [55]; (ii) indirect action, whereby, interaction with nucleic acids leads to deactivation of respiratory enzymes [56]. Te Zn (II) complexes have been found to exhibit antifungal activities against Candida albicans and Aspergillus niger which are around 4 and 10 times higher as compared to antifungal activities of fuconazole against them [57]. Te antimicrobial activity of iron metal complex is due to the presence of quinolones, as they disrupt enzyme production. Chelation also helps increase the bioactivity of the iron metal complex as it enhances lipophilic character of the central metal atom and helps it pass through the microbial membrane quite easily. Te possible mechanism of the bactericidal activity of polymeric ruthenium complex may involve a ROS dependent pathway. It is well-known that ROS such as superoxide anions (O 2 • − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH•) damage lipids, proteins, and nucleic acids in cells, in a process that may lead to cell death [100,101]. Tere is a similarity between Ga (III) and Fe (III) ions, and it is important that Ga (III) can substitute Fe (III) in iron-containing enzymes, thus repressing their activity [102]. Te antimicrobial activity of Ga (III) is counteracted by an excess of Fe (III). Since many iron-containing enzymes are involved in critical functions in bacteria, such as DNA synthesis and repair, metabolism, respiration, and oxidative stress response [103], Ga (III) is likely to cause multiple deleterious efects to bacterial cells. Whether the antibacterial activity of Ga (III) relies on a general perturbation of bacterial iron metabolism or on the inhibition of a specifc enzyme and/or cellular pathway remains an open question. Te antimicrobial activity of the aluminium complexes is based on the chelation theory; chelation reduces the polarity of the metal atom because of partial sharing of its positive charge with the donor groups and possible π-electron delocalization within the whole chelate ring. Also, chelation increases the lipophilic nature of the central atom which subsequently favours its permeation through the lipid layer of the cell membrane [83]. It was proved that antibacterial activity of the Au nanoparticles is due to the attachment of these nanoparticles to the bacterial membrane followed by membrane potential modifcation and ATP level decrease and inhibition of tRNA binding to the ribosome [104].

Pharmaceutical Uses of Metal and Its Complexes
Te metal complexes are nowadays used in the pharmaceutical industries against a number of diseases and are also acting as antimicrobial agents.

4.1.
Antibacterial. Many antibiotics have been tested against many Gram-positive and negative bacteria yielding good results. As seen in case of ciprofoxacin, the antibacterial activity was enhanced by Zn; however, reverse was seen in amoxicillin and penicillin G because of inhibition of DNA gyrase after its penetration in the bacterial cell [105]. Another study showed that the enhanced lipophilicity of the metal complexes such as [cis, fac-RuCl 2 (SO) 3 [107]. Te antibacterial activity is reported to be associated with the terpolymers of 2-amino-6-nitro-benzothiazole-ethylenediamine-formaldehyde against Shigella International Journal of Biomaterials 9 Disturbing respiratory mechanism and blocking metal binding site by delocalization of π-electrons over the whole chelate ring and enhances the penetration of the complexes into lipid membranes [89] 10 International Journal of Biomaterials  [88] International Journal of Biomaterials 11 Disturbing respiratory mechanism and blocking metal binding site by delocalization of π-electrons over the whole chelate ring and enhancing the penetration of the complexes into lipid membranes [1] sonnei, Escherichia coli, Klebsiella species, Staphylococcus aureus, Bacillus subtilis, and Salmonella typhimurium [108]. Urea and its metal complexes after reacting with many metals resulted in formation of 1,3-diethyl-1,3-bis (4nitrophenyl) which exhibits antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Serratia marcescens. Te metallic complexes showed antibacterial activities and better inhibitory efects than ligand and standard drugs. Tis can be explained on the basis of Tweedy's chelation because of which the polarity of metal cation is lessened which is attributed to overlap of ligand orbital and partial sharing of positive charge of the metal ion. Te chelation also enhances the delocalization of p-electrons over the chelate ring, thereby increasing the lipophilicity. Tis results in surging of penetration of complexes into lipid membranes, causing blockage of metal sites in enzymes of the target microbes. Also, the metal complexes inhibit the cell respiration and protein synthesis, thus afecting the growth of microorganism [109].
Te two metal complexes of Cu (II), Zn (II), or Ag (I), namely, zeolite and synthetic zeolite showed antibacterial activity against E. coli. Tis is attributed to their potential of damaging DNA and altering enzyme activity because of increase in reactive oxygen species [110]. However, antibacterial activities against both Gram-positive and Gramnegative bacteria by graphene oxide are also observed. Tis results in damaging of cell membrane and growth inhibition by the oxidative stress, trapping microorganisms within GO sheets, cell membrane damage by sharpened edges of GO, and electron transfer interaction from microbial membrane to GO [111]. However, many metal complexes such as silver, copper, zinc, iron, ruthenium, gallium, bismuth, and vanadium are efective against either Gram-positive or Gramnegative bacteria, while some are efective against both by DNA intercalation [92].
Owing to the presence of the hydroxyl group, Schif ligands have shown better antibacterial activity as compared to other groups against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) Gram-negative bacteria (Escherichia coli, Serratia marcescens, and Pseudomonas aeruginosa) [112]. Even the naturally occurring compound curcumin reacts with metal to form complexes and reactive against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Streptococcus mutans, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Yersinia enterocolitica, and Shigella dysenteriae by the process of membrane disruption by inhibiting ATP-ase activity [88]. Te antibacterial potential of metal complexes when combined with Schif base is enhanced against Bacillus cereus and E. coli. Tis enhanced activity of the complexes may be attributed to chelation of Schif base with metal ions that provide stability and more susceptibility against the bacterial pathogens [113]. Similarly, Schif base (4-chloro-2-{(E)-[(4fuorophenyl) imino] methyl} phenol) when reacting with metal (II) complexes (Mn (II), Co (II), Ni (II), Cu (II), and Zn (II)) show antibacterial activity against both Grampositive bacteria such as Bacillus subtilis and Staphylococcus typhi and Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa [114]. However, bacteria such as Staphylococcus aureus LAC, Streptococcus mutans, and Salmonella enterica are afected by chlorhexidine-cyclamate [115].
Ruthenium complex ([Ru (X-phen) 2 (acac)]+ 1 ) binds to the bacterial surface of Corynebacterium diphtheriae, Mycobacterium tuberculosis, and Staphylococcus aureus and inhibit their growth by interfering in biological processes of growth inhibition by disturbing biological processes [35].
Besides, the addition of silver nanoparticles to the antibiotics has led to the enhanced antibacterial activity against Staphylococcus aureus and Escherichia coli. Tis is because of condensation of DNA molecules for the loss of its replication abilities and interaction of silver ions with thiol groups in protein, which causes inactivation of bacterial proteins [20,116].
Diferent concentrations of silver nanoparticles exhibited antibacterial activity against Gram-positive bacteria irrespective of the pH, incubation temperature, incubation time by inhibited cell division and damaged the cell envelope, and cellular contents of the bacteria also be increasing bacterial cells size, and the cytoplasmic membrane, cytoplasmic contents, and outer cell layers exhibited structural abnormalities [117]. Moreover, tetracycline when combined with silver nanoparticles inhibits the growth of Salmonella typhimurium. Tis is because of the interaction of AgNPs to the bacterial cell wall, which leads to the alteration in membrane structure and enzyme activity [118].

Antifungal.
Metal complexes by various inhibitory unique modes of action exhibit activity against many fungi. Te coumarin complex and its metals such as copper, cobalt, nickel, and zinc exhibit antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus favus, Microsporum canis, Fusarium solani, and Candida glaberata. Te ligands with nitrogen and oxygen donor systems inhibit enzyme activity in fungi thus eradicating them [119]. Similar activity was also observed in sulfonamide which inhibits the growth of Trichophyton longifusus, Candida albicans, Aspergillus favus, Microsporum canis, Fusarium solani, and Candida glaberata [120]. However, 4-methoxy2-amino thiazoles show antifungal activity against Candida albicans and Aspergillus niger because of inhibition of enzymatic activity in them [121]. Ketoconazole, miconazole, and clotrimazole metal complexes are known to possess antifungal activity by the inhibition of thioredoxin reductase enzyme [122]. Copper (II) 1,10-phenanthroline and 2,20-bipyridyl complex shows antifungal activity against Candida albicans and Cryptococcus neoformans by DNA cleavage activity and in silico molecular docking [123]. Copper and its compounds are efective against a wide range of fungi such as Aspergillus carbonarius, Aspergillus fumigatus, Aspergillus niger, Aspergillus oryzae, Candida albicans, Cryptococcus neoformans, Epidermophyton foccosum, Microsporum canis, Myrothecium verrucaria, Saccharomyces cerevisiae, Torulopsis pintolopesii, Trichoderma viride, Trichophyton mentagrophytes, and Tricophyton rubrum [124]. Copper, zinc, gallium, bismuth, and cobalt III based metal complexes show antifungal activity against many diverse fungi by eating up International Journal of Biomaterials fungi [92]. Copper complexes act against Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei by damaging the cell membrane [125]. Metal complexes of peptides are used as antifungal agents by altering the DNA/RNA, protein and cell wall synthesis, permeabilization, and modulation of gradients of cellular membranes [126]. Metal complexes of cobalt when combined with Schif's base display antifungal activity against Candida and Cryptococcus by degenerating the fungal hypha [127].

Antiprotozoan.
Diferent metal complexes act against diferent parasites, protozoa being one of them. Giardiasis, leishmaniasis, malaria, trichomoniasis, and trypanosomiasis are some of the diseases against which new antibiotics drugs have been designed [129]. Antiprotozoan activity was exhibited by silver, copper, and chlorine metal complexes such as Mn (II), Co (II), Pt (II), and Cu (II) complexes. Tey showed an antiprotozoal efect and reduced the protozoal growth in water [130]. However, it also cannot be denied that annually many cases are reported about the increased infection in humans due to Leishmania. Tis can be attributed to nonavailability of antileishmania drugs or costly drugs, resistance, or other such reasons. So, metal complexes of Pt, Cu, Au, Ru, Bi, Tin are being used for drug designing as antileishmania [131]. However, metal complexes are also reported to be efective against Hartmannella vermiformis and Naegleria fowleria [124,132]. So, research in this feld is progressing as antiprotozoal drugs are being designed. Recently, three complexes, namely, [RuCl 3 (trimethoprim) (1,4-bis (diphenylphosphino) butane)], [Cu (CH3COO) 2 (trimethoprim) 2 ], and [PtCl (trimethoprim) (triphenylphosphine) 2 ] PF6 have shown pronounced antileishmania activity [133]. Trypanothione displays a unique pathway and trypanosomatid agent as trypanothione synthetase-amidase and trypanothione reductase enzymes are being designed to control the diseases caused by Leishmania by the residues of redox-active in cysteine and a histidine-glutamate couple (His461′-Glu466′) in trypanothione [134].

4.4.
Antianthelmintic. An upsurge has also been witnessed with the use of antibiotics as antianthelmintic agents. Te paralysing or killing of Pheretima posthuma was witnessed because of 10 diferent compounds of N-benzylidene pyridin-4-amines [135]. Also, the Schif metal complexes of Co II, Cu II, and Ni II exhibited good results against Pheretima posthuma either by paralysing or killing the worm due to DNA cleavage [136]. 4-Aminoantipyrine, a Schif base, is also known for its in vivo and in vitro anthelmintic properties [137]. Extract of silver nanoparticles prepared from silver complexes (silver nitrate) when mixed with extract of M. charantia indicated activity against Pheretima posthuma by the attraction of positive charge on the silver and the negative charge on cell membrane of microorganisms via electrostatic interaction [138].

Disadvantages of Metal Complexes
Metal complexes are a blessing for pharmaceutical industries, but on the other hand, the disadvantages they pose to the health of living organisms and to the environment cannot be ignored.

Cost Efectiveness.
Te bacterial infections arise frequently; therefore, the use of metal complex-based antibiotics is substantially higher in both the developing and the developed nations. For some indicators, the load of ailment is probably lower in one country as compared to others. Maybe at one place, the infection caused by one of the unique bacterial contaminations is probably low, also because of the fast length of the contamination; however, at other places, it can quite be the opposite. Tis may lead to continual conditions with a more widespread efect on the burden of disorder in developing nations than treatable/ acute situations in the developed world. To optimise healthcare world over, it is desirable that policies of spending within reasonable limits be adopted. It also becomes important that new antibiotics are only prescribed when the price is moderate. Value-based pricing is a technique that can be used to decide a price for brand new antibacterial agents at which these drugs provide price for cash which ensures its afordability with uniformity in all the markets worldwide [139]. Moreover, quantifying the economic cost of antibiotics will require innovation within the use of current strategies to lay out studies that correctly gather relevant consequences and similarly research into new techniques for capturing broader monetary efects [140].

Emergence of Antimicrobial Strains.
Te emerging international problem of antimicrobial resistance has more than one aspect and involves resistance against many pathogens. More potent antibiotics, such as carbapenem and colistin, have grown to be a matter of terrifc public health challenges [141]. One common subject matter is that antimicrobial drug use exerts selective stress favouring the emergence of resistance. Terefore, techniques to prevent the improvement and unfold of antimicrobial resistance depend upon the pathogens. Addressing antimicrobial use and resistance is one of the most urgent priorities in confronting rising infectious disease threats [142]. Tose alarming threats are looking for the interest of the clinical community to increase newer antibiotics with long-lasting efcacy, least facet consequences, and occasional fnancial burden. For this reason, rigorous, well-designed, and welldependent studies of exceptionally paramount importance to check the provision of more modern, surprisingly safe, and price efective antibiotics is required [141].

Environmental
Perspective. Due to industrialization, heavy metals from industries move to the environment, resulting in severe environmental contamination. Te modern agriculture techniques are also responsible for accumulation of heavy metal in the environment. Te industrial wastes along with use of fertilizer, pesticides, weedicides, and herbicides cause adverse efects on all living things and their environment [143]. Air, water, and soil each and every part of earth is being contaminated by the heavy metals, thereby disrupting the food chain, causing health problems, and increasing mortality rate in living organisms including humans [144]. Even the elements exhibit speciation in the environment which is another matter of concern [145].
Cr, Ni, Cu, Zn, Cd, Pb, Hg, and As are toxic for the environment due to their accumulation and persistence. Chemicals such as heavy metals, dyes, pathogens, and fertilizers specifcally cause pollution in water, which in turn imbalances the ecological life of humans and other organisms [146]. Water contamination is happening due to accumulation of heavy metals, dyes, and many other contaminants, which are toxic and carcinogenic for the biotic components [147]. In the case of increasing textile industries, not only quality of the waterbody is afected but an increase in the biochemical and chemical oxygen demand (BOD and COD) is seen. Tis largely afects photosynthesis, retards plant growth, enters the food chain, provides recalcitrance and bioaccumulation, toxicity, mutagenicity, and carcinogenicity in living organisms [148]. Cadmium is phytotoxic due to its high mobility in diferent trophic levels which in turn afect plant survival, reproductive success, and migration. And as a result, its diversity and genetic variety decreases [149].
Humans are also gathering antibiotics from the environment which is rendering negative efects on their own health [150]. Tey cause improper functioning of visceral organs, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and muscular dystrophy [151]. Copper, zinc, cadmium, and lead are resulting in anaemia and because of which hypochromic and microcytic patterns are also seen in humans [152]. Cadmium causes respiratory, cardiovascular, and renal efects; chromium causes mental disturbance, cancer, ulcer, and hyperkeratosis; copper causes anaemia, and other toxicity efect includes indirectly through interaction with other nutrients: lead is neurotoxic, nickel causes skin allergies, lung fbrosis, diseases of cardiovascular system, and zinc causes abdominal pain, nausea, vomiting and diarrhoea, irritability, leathery, and anaemia in humans [153]. Besides, hyperpigmentation, keratosis, anaemia, neuropathy, and increased risk of developing several types of cancers in humans are because of these heavy metals [154]. Reactive oxygen species cause cancer. Apoptotic resistance causes cancer, and infammation, epigenetic resistance afect methylation and acetylation. ARH-mediated efects cause serious cancer in humans and female puberty, and increased sensitivity of adipose tissue towards insulin, obesity, and neuronal developmental damage are caused by disruption of endocrine signaling [155,156]. Heavy metal accumulation in the environment is a serious issue for the environment and health of living organisms; they cause serious diseases which cannot even be treated.

Future Prospects
Te applications of metal complexes are still not developed much and, therefore, ofers many opportunities in the coming time. Still, many basic principles for the novel synthesis, designing, and development of metal complexes for pharmaceutical purposes are inadequate. Te burgeoning of many new processes and methods is expected to be helpful for the novel synthesis of the new compounds as therapeutic agents in the coming times.
However, by utilising diverse metal complexes, the underexplored chemical space for drug development can be addressed which opens options for testing of diferent metal complexes to predict their antimicrobial activity. Tis calls for deciphering the mechanism of the active compounds with diferent modes of action. It can be ascertained by fnding out whether the metal complexes are inert which means the ligand stays intact as such but the whole rest of compound binds a specifc bacterial target or partially liable, which means some ligands can get exchanged and produce a species that can binds itself to the microbe or is itself toxic or activity is fully mediated and ligand acts only as a carrier to deliver the metal ion to the target. Keeping in view of this, the mechanism of the diferent metal complexes also needs to be investigated so as to assess their action against diferent organisms in variable conditions. Te selectivity, low toxicity, and in vivo stability of some heavy metals which gets activated in target or diseased tissue certainly makes metal complexes a better option over others, which can be explored, and hence, further improvements can be made for their use as antimicrobials. So, new research needs to be carried out in the coming times to explore new pharmaceutical potential associated with the metal-based complexes.

Conclusion
Te translation of in vitro studies to in vivo experiments and subsequently to human scientifc trials has been the primary mission in the development of new antimicrobial-based metal complexes. It, therefore, becomes vital to increase synthesis of such new metal complexes and to realize and understand their special modes of movement towards resistant pathogens. Combinational drug use can signifcantly deal with the problem, but even this combinational dose pattern may also cause resistance among pathogens. To triumph over the demanding situations of antibiotic resistance, antimicrobial compounds with a new mechanistic method need to be urgently sought. Te future is vivid for this discipline of research, and in the upcoming years, it is expected that more metal complex-based antimicrobial compounds could not only be synthesized but be able to reach the medical trials and fnally to the market.

Data Availability
No data were used to support this study.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
BS and MB conceptualized the study. BS, SS, MB, and MF wrote the original draft of the manuscript. RR and SD reviewed and edited the article. MF, MG, and RKR visualized the study. MB and SS supervised the study. All authors have read and agreed to the published version of the manuscript..