INTRODUCTIONInfectious diseases represent a serious problemworldwide. The growing antimicrobial resistance ofvarious pathogens reduces the efficacy of existingdrugs and preventive treatment, thus fuelling the neverendingsearch for new drugs. Living organisms arein constant contact with a huge number of chemicalcompounds. Some of them are beneficial, e.g. proteins,lipids, carbohydrates, biologically active substances,mineral components, etc., while others are toxic. Peoplein industrial regions are especially vulnerable to thenegative impact of xenobiotics.The antioxidative system of living organismsconsists of the enzymes of oxidismutase, peroxidase,and catalase. It helps to destroy bacteria and substancesabsorbed by leukocyte cells. Antioxidants provideprotection against the damage that results from thecontrolled production of reactive oxygen intermediatesfollowed by lipid peroxidation, protein damage, andDNA rupture. Thus, antioxidants reduce the risk ofchronic diseases, including cancer and heart diseases.Enzymes and oxygen are responsible for regulatedoxygenase and dioxigenase oxidation of biosubstratesin the organism. Biosubstrate comes in direct contactwith oxygen only in the presence of enzymes. Therefore,oxidation processes can be controlled. In case ofdirect contact of the substrate with reactive oxygenintermediates, the redox process proceeds accordingto the radical mechanism, and its rate depends on theconcentration of free radicals in the cell.Radiation exposure causes violation of the redoxtransformations of complexing ions in various biologicalcomplexes. Various radicals and other reactive oxygenintermediates form as a result of the activation anddecomposition of water molecules.Induced cytochrome enzyme system ensures theoxidative transformation of xenobiotics. It triggersthe activation mechanism of the genes responsible forprotein synthesis. Transcription of the correspondingpart of the chromosome starts when the xenobioticbinds to the receptor protein in the cell. Theresulting mRNA leaves the nucleus and becomes thetemplate for the synthesis of the protein componentof the monooxygenase. Drugs, polycyclic aromatichydrocarbons, food components, e.g. flavonoids,xanthines, and indole derivatives, can exhibitmonooxygenase-inducing properties. The intake ofxenobiotics increases the number of monooxygenases,which leads to immunological exhaustion [1].This review features mono- and polynuclearplatinum and palladium complexes with antimicrobialproperties. It contains a comparative analysis ofvarious classes of antibacterial agents, e.g. antibiotics,antioxidant biologically active substances, antimicrobialnanoparticles, nanocomposite materials, biopolymers,micellar systems, and plant extracts.STUDY OBJECTS AND METHODSThe review presents platinum and palladiumcomplexes with antibacterial properties, variouscoordination structure, and different methods of ligandcoordination. The list included mono- and polynuclearcomplexes with the central atom oxidation state of (+2)and (+4). The polynuclear complexes contained bothmono- and polydentate bridging and terminal ligands.For comparison, we examined the main antibacterialagents – antibiotics, antioxidant biologically activesubstances, antimicrobial nanoparticles, and nanocompositematerials, as well as such biopolymers aspolysaccharides, peptides, micellar systems, and plantextracts.The review was based on highly relevant and recentpublications retrieved from the Web of Science, Scopus,and Russian Science Citation Index bases. We limitedthe search to mononuclear and binuclear complexes ofplatinum and palladium and antimicrobial activity.RESULTS AND DISCUSSIONAntibiotics. Antibiotics are natural substances ofmicrobial, plant, and animal origin and products of theirchemical modification that are capable of suppressingthe growth of bacteria, lower fungi, protozoa, viruses,or cancer cells, when administered in low concentrations(10–3–10–2 μg/mL). Science knows several thousandsof natural antibiotics, and almost all of them areheterocyclic compounds. Synthetic and semi-syntheticantibiotics are more active and stable than natural ones.Antibiotics can be divided into four main typesaccording to the mechanism of action: 1) those thatinhibit the synthesis of bacterial cell walls; 2) those thatinhibit template (ribosomal) protein synthesis; 3) thosethat inhibit nucleic acid synthesis; 4) those that inhibitthe functioning of the cytoplasmic membrane (Fig. 1).Antibiotics, antiseptics, bacteriophages, disinfectants,preservatives, and other antimicrobials are used in allindustries. However, large doses of antibiotics and longtreatment sessions may cause allergic or direct toxicreactions that affect kidneys, liver, gastrointestinal tract,central nervous and hematopoietic systems, etc.The European system for surveillance and controlof antimicrobial resistance has identified seventypes of clinically significant bacteria that shape theantimicrobial resistance in Europe: Streptococcuspneumoniae, Staphylococcus aureus, Escherichia coli,Enterococcus faecalis, Enterococcus faecium, Klebsiellapneumoniae, and Pseudomonas aeruginosa.Figure 1 Antibiotics: mode of actionFolic Acid MetabolismTrimethoprimSulfonamidesSulfonesCell wall synthesisCycloserineBacitracinß-lactamsglycopeptidesp-aminobenzoik acidCell membranePolymyxinsFolinic acidProtein synthesisAminoglycosidesMacrolidesLincosamidesStreptograminsAmphenicolTetracyclinesRupirocinDNA-dependentRNA polymeraseRifamycinsDNA replicationQuinolonesDNA NitroimidazolesmRNAFolic acidRibosomes300Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311Strains of microorganisms isolated from variousplant and animal raw materials demonstrate antibacterialproperties, e.g. Bacillus safensis, Bacillus endopheticus,and Bacillus subtilis [2]. Bacteriocins of lactic acidbacteria strains of Lactobacillus delbrueckii B2455,Lactobacillus paracasei B2430, and Lactobacillusplantarum B884 are known to possess an antimicrobialpotential [3].As a rule, antimicrobial activity is determined bythe optical density of culture fluid by using the methodof serial dilutions, as well as the disk-diffusion methodor diffusion E-test. The list of quantitative indicatorsthat describe antibacterial activity includes: minimuminhibitory concentration (MIC); minimal inhibitoryconcentrations that inhibit 50% and 90% of bacteria(MIC50 a nd M IC90, respectively); minimal bactericidalconcentration that causes the complete death of bacterialcells (MBC).Antioxidant biologically active substances.Scientists pay much attention to the antioxidant activityof organic and organometallic compounds against toxicactive forms of oxygen and nitrogen. Antioxidantsprevent oxidative reactions by stabilizing free radicals.However, the necessary amount of antioxidants canbe obtained only with the regular use of biologicallyactive additives. Plant-based bioflavonoids are popularfood additives, e.g. rutin, quercetin, dihydroquercetin,eriodiktiol, resveratrol, etc. [4]. There are complexcompounds that protect DNA from damage in thepresence of hydrogen peroxide [5].The growing prevalence of multiresistant bacterialpathogens has become a worldwide problem in theearly XXI century. Infectious diseases remain aserious problem worldwide. When bacteria, fungi, andparasites become resistant to antimicrobials, it reducesthe efficacy of drugs and preventive treatment. Moreand more microorganisms can withstand vaccinesand antibiotics. For instance, methicillin-resistantStaphylococcus aureus is resistant to vancomycin [6].The World Health Organization has already emphasizedthe need to develop new antimicrobial moleculesbecause conventional antibiotics are growing helpless,especially in fighting the so-called ESKAPE pathogenswith their gradually increasing antibiotic resistance:Enterococcus faecium, Staphylococcus aureus,Klebsiella pneumoniae, Acinetobacter baumanii,Pseudomonas aeruginosa, and Enterobacter [7].Fungal infections also cause high morbidity andmortality, especially in immunocompromised HIVand cancer patients. The growing cancer incidence isanother global health concern as it remains one of themost common causes of death worldwide. The recentadvances in cancer treatment, e.g. chemotherapeuticdrugs, have significantly improved the prognosis andsurvival of cancer patients [7].Antimicrobial nanoparticles and nanocompositematerials. Nanoparticles can target bacteria as analternative to antibiotics. Nanotechnology can beespecially useful in the treatment of bacterial infections.Nanoparticles cover antibacterial coatings of implantabledevices to prevent infection and promote woundhealing. They are used in treating diseases as antibioticdelivery systems. In bacteria detection systems, theyfacilitate microbial diagnostics. They also can controlbacterial infections in antibacterial vaccines [8]. Metalnanoparticles have a pronounced wound healing effect.Nanocomposite materials of silver, gold, platinum,and iron possess high antimicrobial activity whenstabilized by arabinogalactan, which is a naturalpolysaccharide, as well as by other metal nanoclusters.A biologically active complex called FullereneC60/Tween 80 affects the main pathogenesis of woundprocess [9]. There have been studies of the sorptionactivity of Acetobacter xylinum cellulose nano-gel filmsin various biological media in comparison with othersorbents.Antibacterial bimetallic surfaces of implantbiomaterials have also become focus of scientificattention [10]. The research featured platinum and silvernanoparticles that were 1.3–3.9 nm thick and 3–60 nmwide. To create an antimicrobial surface, they weresubjected to magnetron sputtering on a titanium substrate,both separately and together. Sequential sputteringof silver and platinum nanoparticles increased theantimicrobial activity, if compared to co-sprayed silverand platinum samples or pure silver patches (Fig. 2).Researchers have synthesized gold and platinumnanoparticles coated with a pyrimidine-basedligand [11]. The nanoparticles interacted with DNAdue to hydrophobic forces and demoinstrated a goodantioxidant activity. In addition, they possessedantimicrobial properties against Escherichia coli,Klebsiella pneumonia, Pseudomonas fluorescens,Shigella sonnei, Staphylococcus aureus, Aspergillusniger, Candida albicans, Candida tropicalis, andRucoropus mucis indica.Antimicrobial nanoagents can be used in dentistry,medical devices, and food industry [12].Antimicrobial nanoparticles and peptides canbecome new non-antibiotic antimicrobials that killbacteria in biofilms. Biofilms can be produced by severalspecies or one strain of bacteria. A biofilm is a templateFigure 2 Antibacterial activity of silver and platinumparticles [10] coating of one or more strains of bacteria that adhere tobiological or non-biological surfaces. Biofilms increasethe resistance of microorganisms to antimicrobial agentsby producing extracellular polymeric substances.Many bacterial pathogens have developed antibioticresistance, resulting in infections that cannot be treatedwith conventional antibiotics. New non-antibioticantimicrobial agents, e.g. silver nanoparticles or newantimicrobial proteins, can bind and oxidize thiolgroups, block DNA replication, alter the expression ofbacterial genes and denaturing enzymes, induce reactiveoxygen species, or damage bacterial membranes.Antimicrobial proteins, e.g. antimicrobial peptides, andnatural enzymes, e.g. those derived from insects andbacteria, also demonstrate antibacterial properties [2, 3].As a result, they can be used in biomedicine and foodindustry as antibacterial agents. The antimicrobialproperties of peptides are not as strong as those ofconventional antibiotics, but sufficient enough to killpathogenic microorganisms. The mechanisms of theiraction remain unclear, but they are believed to targetbacterial membranes and intracellular molecules.Chronic infections lead to inflammation and depleteimmune defense, thus contributing to the proliferationof cancer cells. Cisplatin (CDDP) has been approvedby the Food and Drug Administration (FDA) as anantitumor drug, which is now widely used to treatvarious types of cancer. Cisplatin owes its antitumorproperties to the fact that it affects DNA directly [13].DNA alkylation suppresses the biosynthesis ofnucleic acids and kills the cell. However, cisplatinhas no targeted effect: it spreads in all biologicalfluids and body tissues, causing renal functionimpairment, anaphylactic reactions, leukopenia,thrombocytopenia, anemia, and neuropathy [14].The antiproliferative effect that cicplatin produces onrapidly dividing cells explains its toxic impact on thefunctional state of organs and tissues.As a result, scientists around the world have beentrying to develop more effective antitumor platinumbaseddrugs with fewer complications. Currently, it isone of the most urgent tasks of bioorganic chemistryand biotechnology. The introduction into the internalsphere of a complex of powerful antiproliferative andfunctionally active ligands is another strategic directionin the search for methods of highly effective agents.Structural analogues of clinically tested platinumcomplexes have been subjects of numerous studies in therecent decades. Most of them feature monofunctionalplatinum (II) complexes that carry only one labileligand, each complex binding to DNA only once [15].The nature of the ligand and its coordination typeaffect the reactivity of the central atom. Coordinationchanges not only the thermodynamic stability andkinetic lability of the complex, but also its lipophilicproperties. It either stabilizes or destabilizes theoxidative state of the central atom.Biopolymers: polysaccharides and peptides.Micellar systems. Metals can produce complexbiologically-active biopolymers with antimicrobial andantitumor properties.Galactan-containing polysaccharides are known fortheir high biological activity and immunomodulatoryeffect. Arabinogalactans contain numerous galactoseand arabinose residues, which allow them to interactwith asialoglycoprotein receptors. This valuable propertymakes it possible to use these polysaccharides to deliversubstances that are unable to pass through the outermembrane into the cell. For instance, Starkov et al. usedarabinogalactan to deliver platinum into tumor cells [16].Platinum has an antitumor effect as part of cisplatin,which is widely used in cancer treatment [14]. Starkovet al. also proved the antitumor effect of the equimolarplatinum-arabinogalactan complex based on theinteraction of cis-diamine(cyclobutane-1,1-dicarboxylate-O,O’)platinum (II) with a polysaccharide [17].Popova and Trifonov analyzed research resultspublished over the past 15 years which featured thesynthesis and biological properties of analoguesand derivatives of amino acids with tetrazolylfragments [18]. They concluded that tetrazolyl analoguesand derivatives of amino acids and peptides have agreat potential for medical chemistry. Tetrazoles arepolyazitous heterocyclic systems which include fourendocyclic nitrogen atoms. They are able to exhibit theproperties of acids and bases, as well as form stronghydrogen bonds with proton donors and, less often, withproton acceptors. They are metabolically stable and canpenetrate biological membranes. Another promising areais the synthesis of linear and cyclic peptides based onmodified amino acids with a tetrazolyl fragment. Finally,some tetrazole-containing amino acids and peptidespossess a high biological activity and can become asource of new drugs [18].Porphyrins are tetrapyrrole compounds thatform metal porphyrins when interacting with metalcompounds, and metal porphyrins can easily enter intoelectrophilic substitution reactions. In addition, free andmetal-bound porphyrins are easily reduced to producemono- and dianionic compounds. Their nucleophilicproperties allow them to interact with proton donors.Simulated solutions of porphyrin compounds help studyphoto-oxygenation.Platinum-bound porphyrins can inhibit multiresistantbacteria, e.g. Staphylococcus aureus [19].Tetra-platinum (II) porphyrin increased its hemolyticactivity when exposed to light. Lopes et al. provedthat platinized porphyrins had a good potentialfor wastewater treatment, biofilm control, andbioremediation since they can be used for microbialphotodynamic inactivation [19].Proline derivatives are known to possessantibacterial activity. Thioproline is an antioxidant,while phenylproline derivatives inhibit the Staphylo302Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311coccus aureus sortase SrtA isoform [20]. Gram-positivebacteria produce surface proteins that promote theattachment of the bacterial cell to the host and preventphagocytosis. During catalysis, sortase enzyme sortssurface proteins on the bacterial cell wall. Surfaceproteins then bind covalently to the bacterial cell wallthrough the catalyzed S. aureus SrtA transpeptidasereaction. Deactivation of SrtA genes of gram-positivemicroorganisms inhibits the fixation of surface proteinsand reduces the virulence of the bacterium. Antibioticsare not the only S. aureus SrtA inhibitors: peptides,plant extracts, and low-molecular-weight organiccompounds have the same properties [20].Therefore, biopolymers and micellar systems withtheir ability to penetrate biological membranes candeliver metal complexes into cells.Complex platinum and palladium compounds.Drugs based on organic ligand complexes exhibita greater antimicrobial effect compared to organicpharmaceuticals. Complexation produces a synergisticeffect between the organic ligand and the complexingagent. Chelates of platinum, iron, iridium, rhodium,ruthenium, palladium, cobalt, and nickel have areputation of effective therapeutic agents.Metal-containing active centers with a stable,inert, and non-toxic nature are quite rare in biologicalsystems. They owe their activity to the bioavailabilityof the complexes. Metal complex-based drugs facilitatethe transport of organic ligands towards the bacterialcell. Palladium complexes proved highly effectiveagainst resistant forms of microorganisms. For instance,tetracycline palladium (II) complex appeared sixteentimes more effective against tetracycline-resistantbacterial strains of E. Coli HB101/pBR322 thantraditional drugs [6].There are a huge number of pharmacologically activeheterocyclic compounds. Advanced medical chemistryhas made it its main task to study the antimicrobialand antitumor properties of platinum and palladiumcomplexes with heterocyclic ligands.Benzothiazole derivatives are one of the mostpopular pharmacologically known heterocycliccompounds. Benzothiazole and its analoguesdemonstrate a wide range of biological properties, e.g.antitumor, antimicrobial, anticonvulsant, antiviral,antituberculous, antimalarial, anthelmintic, analgesic,anti-inflammatory, antidiabetic, fungicidal, etc. [21].Thiazole nuclei that can be coordinated to metal atomsare often used as an ambidentate ligand in biologicallyactive complexes.Thiosemicarbazone and its derivatives can be usedas synthetic antiviral agents. They are heterocyclicligands and contain nitrogen, sulfur, and oxygen donoratoms. Platinum (II) and palladium (II) complexes withthiosemicarbazones exhibit anti-tuberculosis activityagainst Mycobacterium tuberculosis [22].Suleman et al. described Schiff-base complexes thatcontained donor atoms of nitrogen, sulfur, and oxygenand possessed antimicrobial and antitumor activity. Theantibacterial activity of these multi-dentate ligands andtheir complexes demonstrated great prospects pharmacyand agricultural chemistry. Coordination compoundsof transition metals owe their unique configuration andchemical lability to their specific electronic and stericproperties, which make them sensitive to the molecularenvironment [23].The antimicrobial and antitumor properties of thesecomplexes depended on the electron-donor and acceptorsubstituents in the aromatic ring. Bioligands modified byhydrophilic groups appeared to increase the solubility ofcompounds [24].Platinum (II) complexes obtained fromfunctionalized aroylaminocarbo-N-thioyl prolineatesalso demonstrated antibacterial and antifungalproperties [25]. Sulfur and oxygen atoms allowedaroylaminocarbo-N-thioyl ligands to coordinatebidentally. Non-electrolyte complexes had a squareplanarconfiguration.Mawnai et al. synthesized complexes withN-coordinated pyridylpyrazolyl ligands that formeda six-membered metallocycle [26]. They conductedin vitro studies of the antibacterial activity of ligandsand their complexes. The research featured bothgram-negative (Escherichia coli and Pseudomonasaeruginosa) and gram-positive (Staphylococcus aureusand Bacillus thuriengiensis) bacteria. The cationicnature of the complexes made them more effectiveagainst the gram-negative bacteria.Bakr et al. synthesized organometallic platinumand palladium complexes with heterocyclic derivativesof pyrazolone [5]. Pyrazolone derivatives had a fivememberedring with an additional keto group, whichallowed them to form chelates. They studied thebiological activity of azo-compounds to use them asantitumor, antioxidant, and antimicrobial agents. Theyalso assessed their nuclease activity against DNA.They performed an MTT lab-test on four humancancer cell lines to study the antitumor activity ofthe compounds in question. The cell lines includedhepatocellular carcinoma (HePG-2), colorectal cancer(HCT-116), human prostate carcinoma (PC-3), and breastcarcinomas (CMC-7) [5].As a rule, researchers employed standard methods tostudy the antimicrobial activity of the abovementionedcompounds, e.g. the cut-plug method. Some experimentsfeatured strains of pathogenic bacteria, e.g. Escherichiacoli, Staphylococcus aureus, Bacillus subtilus,Salmonella typhi, and Proteus spp, or such maliciousfungi as Candida albicans and Aspergillus niger [5]. Anin vitro anntioxidant analysis of pyrazolone derivativesand their metal complexes made it possible to comparethe results of erythrocyte hemolysis. The palladiumcomplexes demonstrated a greater antioxidant activityin comparison with platinum complexes. The freeligand had a more prominent increase in the antioxidant303Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311activity, compared to metal complexes. This result couldbe explained by a greater ability to charge transfer of thecondensed ring system. It increased the ability of theheterocycle to stabilize unpaired electrons of the azocompound,thus binding free radicals.Chitosan is an antimicrobial agent that can destroybacteria, filamentous fungi, and yeast. Chitosan isa copolymer of 2-amino-2-deoxy-D-glucopyranoseand 2-acetamido-2-deoxy-D-glucopyranose combinedwith β (1 → 4), which gives it high biocompatibilityand biodegradability. Chitosan is widely used in foodindustry, agriculture, and medicine.The antimicrobial activity of chitosan and itsderivatives depend on pH, type of microorganisms,molecular weight of the biopolymer, and the degreeof its deacetylation. If a chemical change occurs inthe structure of the amino- and hydroxyl groups ofthe glucosamine chains of the biopolymer, it canaffect not only the solubility and stability of chitosan,but also its antimicrobial activity. Berezin et al.described the synthesis of water-soluble conjugatesof chitosan with tetrazoles. They bound tetrazoles bythe chlorohydroxypropyl groups of N-(3-chloro-2-hydroxypropyl) chitosan, while the other part of thegroups interacted with the amino groups of the polymer,which led to intra- or intermolecular crosslinking [27].The antimicrobial properties increased as a result of thecomplexation of chitosan with various metals.Barbosa et al. developed new platinum (II) andpalladium (II) complexes with biopolymer amphiphilicSchiff-bases to increase the biological activity ofchitosans. They performed the binding by fixingchitosans in templates of various molecular weights.The chitosans were modified with salicylic aldehydeand glycidol [24]. They introduced salicylaldehyde toobtain the complexing Schiff-base sites in the chitosantemplate. Glycidol made it possible to increase thewater solubility of the resulting biopolymer complexes.The new complexes underwent spectral and thermaltesting for antimicrobial and antitumor activity.When compared to the free ligand, the complexesdemonstrated a higher antibacterial efficacy againstgram-negative bacteria Pseudomonas syringae thanagainst Fusarium graminearum fungi. They alsodemonstrated a high antitumor effect on MCF-7 breastcancer cells, with certain selectivity for non-tumor cells(Balb/c 3t3 clone A31) depending on the concentrationand molar mass. In higher concentration, all complexessynthesized with different molecular weights of thepolymer template decreased the viability of MCF-7cancer cells [24].Bobinihi et al. synthesized dithiocarbamideligands based on primary amines, N-phenylaniline,4-methylaniline, and 4-ethylaniline [28]. S,S-bindingresulted in bidentate coordination, which led to theformation of squared complexes of platinum (II)[Pt (L) 2] and palladium (II) [Pd (L) 2]. They exhibitedantimicrobial activity against gram-negative bacteria(Escherichia coli, Klebsiella pneumonia, and Pseudomonasaeruginosa), gram-positive bacteria (Bacilluscereus and Staphylococcus aureus), and fungi (Candidaalbicans and Aspergillus flavus).The mechanisms of the antitumor effect changedwhen naphthalenbenzimidisole was introducedas a ligand into the platinum-metal system. Theantiproliferative activity, drug resistance, and toxicityincreased. Liang et al. invented a synthesis method fornaphthalene benzimidisole-platinum (II) complexes [29].They studied their antiproliferative activity for eightcancer cell lines, namely Hela, HepG2, SKOV3,NCI–H460, BEL–7404, SMMC–7721, U251, and A549.Unlike cisplatin, the naphthalenbenzimidisole complexesdid not show resistance to A549-CDDP. The mechanismof the antitumor effect appeared due to the covalentbinding to DNA and an increase in the expression levelof intracellular type I. An in vitro experiment showedthat several complexes proved sensitive and selectiveto cell lines SMMC-7721 and U251 and possessed lowtoxicity to normal HL-7702 cells.Antimicrobial activity depends on the alkyl chainlength of N-substituted imidazolium salts, wherelong alkyl chain compound with 8–16 carbon atomsreached the lowest values of the minimum inhibitoryconcentration. While alkyl chains under six carbonatoms are usually inactive, the alkyl chain length affectsthe functioning of the bacterial membrane [30, 31].When a long hydrocarbon chain integrates with alipid bilayer of the cell membrane, cell contents maystart leaking out [32]. The antimicrobial activityof imidazolium salts depends on such factors ashydrophobicity, adsorption, critical micelle concentration,and the transport rate in aqueous media.Meng et al. synthesized a number of platinum (II)complexes with substituted 3-(2’-benzimidazolyl)coumarins (1-benzopyran-2-one) [33]. The complexesexhibited a high cytotoxic activity in vitro againstcisplatin-resistant cancer cells, namely SK-OV-3/DDPwith a low IC50.Choo et al. described a wide range of organometallicdrugs with N-heterocyclic carbene (NHCs) ligands [34].The new complexes were insoluble in most solventsexcept dimethyl sulfoxide. Complexes with severalconjugated rings are highly hydrophobic and do notaffect the activity of gram-negative bacteria. Inhibitionof the growth of gram-positive bacterial strains occursat low micromolar concentrations of the synthesizedcomplexes. The different susceptibility of grampositiveand gram-negative bacteria results from theirmorphological differences, namely the permeabilityof the outer layer of bacteria. The difference insusceptibility can be explained by their morphologicaldifferences between gram-positive and gramnegativebacteria. Gram-positive bacteria have a lowerpermeability of the outer peptidoglycan layer, whilethe outer membrane of gram-negative bacteria containsstructural lipopolysaccharide components. They makethe cell wall impervious to lipophilic solutions. As aresult, porins, membrane transport proteins, form aselective barrier for hydrophilic solutions [34]. Thepart of the channel protein that is responsible fortransmembrane transport opens and closes depending onthe hydrophilicity of the complex.The synthesis of platinum (IV) antitumor drugprecursors relies on the fact that the oxidation stateof platinum (IV) leads to a greater stability than theirplatinum (II) analogues. The stability of platinum (IV)precursors results from their resistance to reduction,inertness to ligand exchange, and reactivity [35].There have been successful attempts to synthesizeantimicrobial platinum complexes with coumarinderivatives as heterocyclic biologically activeligands [36]. They inhibited the cyclooxygenase enzymeby coumarin complexes of platinum (IV) with cisplatinand oxaliplatin centers.Oxygen atoms allow carboxylate ligands of RCO2–to possess electrodonor properties. Their coordinationis monodentate, bidentate, and even tetradentate.The carboxylate platinum and palladium complexesare analogues of biologically active compounds. Theacidoligand and synthesis conditions proved to affectthe formation of the internal coordination sphere.The system of hydrogen bonds and/or π – π-stackinginteractions between aromatic ligand segments alsoproduced a certain effect on the processes of selforganizationof complexes into supramolecularstructures [37].Carboxylate metal complexes often take the form ofpolynuclear compounds due to the oligomerization ofoxo- and hydroxo-functional groups, thus developingМ-О-M structural units. There are platinum (IV)carboxylate complexes with anticancer activity [35, 38].Al-Khathami et al. synthesized several Schiff baseswith various primary aromatic amines derived frompyridine-2-carboxaldehyde as ligands for platinum(II) complexes [39]. They studied their antimicrobialactivity in vitro using the cut-plug method in nutrientmedia. Microorganisms were plated in wells filledwith the test solution of ligands and complexes withsubsequent incubation. Some complexes and ligandsproved to have inhibitory effect on such pathogenichuman bacteria as Escherichia coli, Bacillus subtilus,Salmonella typhimurium, Klebsiella pneumoniae,Staphlococcus aureus, Pseudomonas aeruginosa, andCandida fungus. Studies of DNA binding showed thatthe electron-withdrawing groups facilitated the bindingof platinum (II) complexes containing the Schiffbase pyridyl ligands (Fig. 3). The complexes with anelectron-withdrawing group demonstrated the highestantimicrobial effect. The complex with a nitro groupproved effective against bacteria, but not against fungi.The acetyl group increased antimicrobial activity againstalmost all strains. Due to the hydroxyl group, freeligands possessed a higher antimicrobial activity againstgram-negative bacteria, compared to their platinum (II)complexes.Platinum complex compounds are not the onlyplatinum group metals with pronounced antimicrobialand antitumor properties. Gold, silver, iridium, rhodium,and ruthenium complexes demonstrate similar activities.The cytotoxicity of gold complexes usually consists inthe inhibition of thiol-containing enzymes. When goldbinds with thiol groups, the reductases and proteases ofcancer cells become potential targets for gold complexes(Fig. 4). Inhibition of the activity of these enzymescan disrupt the redox state of the cell and increase theproduction of reactive oxygen species (ROS), thuscausing cellular oxidative stress and leading to itsown apoptosis. This mechanism differs from that ofplatinum-based drugs [40].Polynuclear platinum and palladium complexes.Binuclear and polynuclear platinum complexes haverecently proved biologically active and antimicrobial.Bridging ligands contribute to the formation ofcyclometallic complexes. Polynuclear compoundsexhibit properties different from those of free ligandsand monomeric complexes.Johnstone et al. studied non-classical platinum (II)complexes with trans-geometry or a monofunctionalFigure 3 Methods of binding a mononuclear complex witha protein [39]Figure 4 Binding of silver with thiol groups [40]305Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311coordination center, as well as polynuclear platinum (II)compounds, platinum (IV) prodrugs, photoactivatedplatinum (IV) complexes, and other precursors [41].Ligands and complexes differ in chemicalnature, size, and geometric shape, which affect theirDNA-binding properties. A detailed study of the methodof binding polynuclear complexes of platinum withDNA produced a mixed result. The complexes were ableto interact directly with DNA due to covalent binding,electrostatic forces, or intercalation [42]. Groove bindingproved to be the cause of cell apoptosis [43].Complexes owe their activity to the formation of newadducts with DNA. As a result, there are three importantaspects to their binding: DNA pre-association, formationof DNA adducts, and induced conformational changesin DNA [44]. Multinuclear platinum complexes containtwo or more bound platinum centers that can covalentlybind to DNA and, therefore, are capable of forming acompletely different kind of DNA adducts comparedto cisplatin and its analogues. Multicore complexesrepresent a completely new paradigm of biologicallyactive complexes, in particular, for platinum-basedanticancer agents.In our previous research, we proved that the bonds ofbridged halide ligands had a greater lability, comparedwith the terminal ones [45]. This fact made it possibleto introduce polynuclear platinum complex compoundsinto the biosystem. Their aquatization resulted ina break of bridging bonds with the formation ofmonomeric complexes.P,N- and S,N-bidentate ligands have the propertiesof both soft and hard bases. As a result, they candirect organization of the metal coordination sphere(Fig. 5), as well as form bimetallic and polynuclearsystems [43].In our previous studies, we also described amethod for the synthesis of binuclear complexes ofdivalent platinum. According to this method, aminoacids (glycine, alanine, and valine) bound with twocentral atoms simultaneously via two donor atoms, i.e.bridges [(NH3)2Pt(μ-N,O-L)2Pt(NH3)2](NO3)2 [46]. Thecoordination of amino acids led to the formation ofchelates, while the presence of a biogenic ligand in theinternal coordination sphere reduced the overall toxicityof the platinum complex. The compounds showedcytotoxic activityI.Popova and Trifonov synthesized antimicrobialbinuclear platinum (ΙΙ) complexes with tetrazoleand 5-methyltetrazole with the composition of cis-[{Pt(NH3)2(L-H)Cl}2]Cl [18].Lunagariya et al. studied the antibacterial activityof platinum (II) binuclear complexes based on pyrazolo[1,5-a] pyrimidine with neutral tetradentate ligands.The general formula was [Pt2LCl4] [42]. The researchfeatured five test organisms: two gram-positive(Bacillus subtilis and Staphylococcus aureus) andthree gram-negative (Escherichia coli, Pseudomonasaeruginosa, and Serratia marcescens). It also includedan in vitro study of anti-tuberculosis activity againstMycobacterium tuberculosis H37Rv strain.Antibacterial actions include several phases ofinhibition: cell wall synthesis, cell membrane functions,protein synthesis, nucleic acid synthesis, and folicacid synthesis. Chelation makes it possible to increasethe values of the minimum inhibitory concentrationof the complexes. This effect can be explained by theTweedy’s chelation theory: chelation allows the complexto penetrate the cell membrane. The complexes aretoxic partially because the metal-ligand bond is strong.The toxicity differs from the type of substituent presentin the synthesized compounds (Fig. 6) [42]. Activesubstituents in ligands have a high lipophilicity, whichallows them to penetrate the complexes through the cellmembrane. Complexes with a high-electronic substituentNO2– in its phenyl ring exhibit a greater antibacterialand anti-tuberculosis activity. Nitro groups act aschemical isosteres for oxygen atoms in the heterocyclicbase of thymidine. However, they also participate inthe “strong” O – H bond. As a result, the bond exhibitsgreater DNA-binding and antimicrobial activity thanother complexes. The phenyl group is replaced withdonor substituents, e.g. methoxy- or methyl group, anda hydrogen atom in the para position. Subsequently,the antibacterial activity against P. Aeruginosa andE. coli decreases, while acceptor chloro-, nitro-, andfluorosubstituents increase their efficacy againstS. Marcescens and B. Subtilis [42].Rubino et al. synthesized binuclear platinum (II)complexes with fluorinated heterocyclic ligands:5-perfluoroalkyl-1,2,4-oxadiazolylpyridine and 3-perfluoroalkyl-1-methyl-1,2,4-triazolylpyridine [47]. Chlorineatoms served as bridges between the two platinumatoms. The complexes showed antimicrobial activityagainst Escherichia coli, Kocuria rhizophila, and twostrains of Staphylococcus aureus. Azolate-bridgedpolynuclear platinum complexes formed DNA adductsas a result of additional electrostatic interaction.I Salishcheva OV, Moldagulova NE, Proskynov IV. Investigationof the biological activity of organometallic complexes of platinum.XXI Mendeleev Congress on General and Applied Chemistry; 2019;St. Petersburg. St Figure 5 Binding of DNA with binuclear complex [43] . Petersburg, 2019. p. 334.306Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311Icsel et al. obtained mono- and binuclearpalladium (II) and platinum (II) complexes withligands L1 = 5,5-diethylbarbiturate and pyridinederivatives L2 = 2-phenylpyridine, 2,2’-bipyridine and2,2’-dipyridylamine. The general formula was [M(L1-N)2(L2-N,N′)] and [M2(μ‑L1-N,O)2(L2-N,C)2] [48]. Thecomplexes appeared to have similar DNA bindingmechanisms.There have been much fewer medical studiesconcerning palladium (II) complexes for medicinaluse. Palladium (II) and platinum (II) complexes havedifferent chemical properties because palladiumcompounds have a greater lability of the ligandcomplexingbonds. As a result, hydrolysis processes getaccelerated, and the amount of dissociation productsincreases, e.g. aqua- or hydroxo-complexes, which areunable to fulfill their biological functions. To eliminatethis factor, large heterocyclic and chelate ligands have tobe introduced into the internal sphere.Rubino et al. synthesized antibacterial palladiumcomplexes with aromatic nitrogen, sulfur, and oxygencontainingligands. They described the synthesis ofbinuclear platinum (II) and palladium (II) complexeswith the 2,2’-dithiobis-benzothiazole (DTBTA) ligand[Pd2(μ-Cl)2(DTBTA)2]Cl2. The research included anin vitro analysis of their antitumor activity againsthuman breast cancer (MCF-7) and hepatocellularcarcinoma (HepG2), as well as against Escherichia coliand Kokuria rhizophila. The complexes proved to havea greater antimicrobial effect against gram-positivebacteria than cisplatin. The low activity against gramnegativebacteria was explained by the fact that thesebacteria have an additional outer membrane, which caninterfere with the absorption of both compounds.Terbouche et al. studied palladium (II) andruthenium (III) binuclear complexes with phenylthioureaderivatives, namely their antibacterial properties,antioxidant activities, and stability (Fig. 7) [49]. Theyused the spectrophotometry method to assess theformation constants of the new Schiff-base alkali metalcomplexes and the systems formed by these chelates andcholesterol.Chakraborty et al. described the synthesis andcharacteristics of binuclear palladium (II) complex[(3,5- dimethylpyrazole)2Pd2(μ-3,5-dimethylpyrazolate)2(2,6-dipicolinate)] [50]. It was a dimer connected bytwo 3,5-dmpz units. One palladium atom containedtwo protonated 3,5-Hdmpz ligands and the other – onebidentate 2,6-dipicolinate, which made the complexasymmetric. The central nucleus of Pd2N4 consisted ofsix elements. It was a boat-like structure with palladiumatoms located at the tops. The molecules assembled inan elongated zigzag one-dimensional network formedby 3,5-Hdmpz-carboxylate (2,6-dipic 2-) hydrogenbonds. The complex demonstrated antimicrobialactivity against Bacillus subtilis, Escherichia coli,and Aspergillus niger. The minimum inhibitoryconcentration was 100 μg/mL.Another study featured pyrazolate binuclearPalladium (II) complex [Pd2(μ-dppz)2(Hida)2]·CH3ОН·2Н2O (dppz = 3,5-diphenylpyrazolate) withmonoprotonated iminodiacetate (Hida). It demonstratedantimicrobial activity against Bacillus subtilis [51]. Thedonor atoms of oxygen and nitrogen coordinated thepyrazolate ligand.A binuclear pyrazolate square-planar palladiumcomplex Pd2Cl4L2 (L = 5-methyl-5-(3-pyridyl)-2,4-imidazolidenedione ligand) with cis- and transconfigurationsalso showed antimicrobial activity [52].The trans-isomer appeared more stable in the liquidand gaseous phase than the cis-isomer. The pyridinetypenitrogen atoms provided for the square-planargeometry around the metal center. Each palladiumatom was coordinated by one nitrogen atom and threechlorine atoms, one serving as terminal and two asbridging ligands (Fig. 8). The initial mononuclearcomplex and the binuclear palladium complex weretested for antibacterial activity against six types ofmicroorganisms: Staphylococcus aureus (ATCC 6633),Staphylococcus saprophyticus (ATCC 15305), Escherichiacoli (Lio), Proteus vulgaris (Lio), Serratiamarcescens (PTCC 1330), and Bacillus cereus (ATCC7064). Bacterial growth was studied by disk diffusion,while the minimum inhibitory concentration of theFigure 6 Coordination of tetradentate pyrazolo-pyrimidinein the binuclear platinum (II) complex [42]Figure 7 Tridentally coordinated bis-[1-(2-[(2-hydroxynaphthalen-1-yl)methylidene]amino}ethyl)-1-ethyl-3-phenylthiourea]ligand in a binuclear palladium (II) complex [49]307Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311chemicals was determined by in vitro dilution. Themicroorganisms were cultured in harvest broth andnutrient agar (Oxoid Ltd.). The agar culture mediumincluded 0.5% of peptone, 0.3% of beef or yeastextract, 1.5% of agar, 0.5% of NaCl, and distilled water;pH = 6.8 at 25°С [52].The compounds inhibited the metabolic growth ofbacteria to varying degrees. The binuclear complex hada higher activity compared to the free ligand, whilethe ligand activity became more pronounced whencoordinated with the metal. The increased activity ofmetal chelates could be explained by Tweedy’s chelatetheory: the polarities of the ligand and the complexingagent are restored by balancing the charges throughoutthe whole chelate ring. As a result, the lipophilicnature of the metal chelate increases and facilitatesits penetration through the lipid layer of the bacterialmembrane [53].Plant extracts. Natural products or their extractspossess antimicrobial properties, e.g. grape skin oressential plant oils, e.g. of citrus fruits, wormwood,mint, and ginger [54–57]. When used in combinationwith nanoparticles, various functional essential oilsproduce a synergistic effect against multidrug resistantmicrobial pathogens (Fig. 9) [58].CONCLUSIONMalicious microorganisms keep mutating. Theygrow ever more resilient to drugs, which triggers anever-ending search for new antimicrobial agents.Drugs based on organic ligand complexes exhibit anantimicrobial effect comparable to that of antibiotics.The complexation leads to a synergistic effect betweenthe organic ligand and the complexing agent. Chelatesof platinum, palladium, silver, iron, iridium, rhodium,ruthenium, cobalt, and nickel are therapeutic agents.Complexes with enhanced bioavailability have a betterantimicrobial effect against pathogenic microorganisms.Metal-based drugs facilitate the transport of organicligands towards the bacterial cell.The reactivity of the central atom depends on thenature of the ligand and the coordination method.Coordination changes not only the thermodynamicstability and kinetic lability of the complex, but alsothe lipophilic properties that ensure the ability of thecomplex to penetrate the cell membrane. It stabilizesor destabilizes the oxidative state of the central atom.When complexes with functional multi-dentateligands enter the internal sphere, it enhances theantimicrobial effect. The presence of a biogenic ligandin the coordination sphere reduces the general toxicityof platinum and palladium complexes. Drugs basedon complexes with functional multi-dentate ligandsexhibit a greater antimicrobial effect compared to freeligands. Inhibition of bacterial growth occurs at lowerconcentrations of metal complexes.Active metal centers with a stable, inert, and nontoxicnature are of great value for biological systems.Polynuclear and heteronuclear complexes increasethe number of active centers that block the action ofbacterial cells and improve the formation of cross-linksbetween different molecules. These valuable propertiesFigure 8 Binuclear pyrazolate square-planar palladiumcomplex Pd2Cl4L2of (trans-configuration) with bridgingchloride ligands [52]Figure 9 Antimicrobial effect of nanoparticles used with functional essential oils [58]encourage researchers to synthesize new complexeswith antibacterial and antitumor properties. Due totheir ability for covalent binding to bacterial cell DNA,polynuclear platinum and palladium complexes containtwo or more bound metal centers that can form acompletely different kind of DNA adducts, as comparedto mononuclear precursors.The biological activity of structural analogues ofclinically approved platinum complexes has been focusof scientific attention in the recent decades. A furthersynthesis of complex antimicrobial compounds usedin combination with other agents may help to build upa rich bank of substances with a great antimicrobialpotential. In the long term, further studies of theirantimicrobial action and the way it changes undervarious factors will make it possible to promptlyovercome local or global outbreaks of infectiousdiseases, such as the current pandemic.CONTRIBUTIONAuthors are equally related to the writing of themanuscript and are equally responsible for plagiarism.CONFLICT OF INTERESTThe authors declare that there is no conflictof interest regarding the publication of this article.