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Olar, R. Complexes with Antibiofilm Activity. Encyclopedia. Available online: https://encyclopedia.pub/entry/20278 (accessed on 19 June 2024).
Olar R. Complexes with Antibiofilm Activity. Encyclopedia. Available at: https://encyclopedia.pub/entry/20278. Accessed June 19, 2024.
Olar, Rodica. "Complexes with Antibiofilm Activity" Encyclopedia, https://encyclopedia.pub/entry/20278 (accessed June 19, 2024).
Olar, R. (2022, March 07). Complexes with Antibiofilm Activity. In Encyclopedia. https://encyclopedia.pub/entry/20278
Olar, Rodica. "Complexes with Antibiofilm Activity." Encyclopedia. Web. 07 March, 2022.
Complexes with Antibiofilm Activity
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Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3d ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. 

anti-biofilm activity complex extracellular polymeric substances mechanism of action metallic ion microbial target

1. Introduction

Infectious diseases remain at the top of the list of mortality and morbidity causes, resulting from many converging factors such as global emergence and the spread of genetically encoded resistance to all currently used antibiotics, the delays in the discovery of novel antimicrobials, and complications associated with biofilm development on tissues and prosthetic devices [1][2]. Microbial biofilms represent the most frequent lifestyle of microbial cells in the natural environment, and in the case of pathogenic microorganisms, they protect them from adverse environmental conditions, representing both reservoirs and sources of disease outbreaks, especially in the case of medical devices [2].
The research in the field demonstrates that most bacteria, including the antibiotic-resistant ones, and some fungi could develop biofilms. Moreover, the formation of a mixed biofilms has been reported, such as Candida–streptococcal associations in the case of oral diseases [3]. These represent a microbial derived complex sessile community in which the microorganisms adhere irreversibly to an inert or living surface as well as an interface and to each other and are embedded in a matrix of self-generated extracellular polymeric substances (EPS) [4].
This microbial lifestyle is involved in the majority of chronic and hard to treat microbial infections, especially those associated with the healthcare system [5][6]. Microbial biofilms can form on living tissue, resulting in wound infections [7], endocarditis or lung infections in cystic fibrosis patients [6], as well as on medical devices such as stents, catheters, and prosthetic and dental implants [8].
Biofilm-embedded cells are generally much more tolerant to both antibiotics and the immune system in comparison to their planktonic counterparts [1][6][9]. The biofilm resistance towards antibiotics could be between 100–1000 fold higher in comparison to planktonic cells [10], and moreover, some antibiotics at sub-inhibitory concentrations can promote biofilm development [11]. This enhanced phenotypic resistance results from several mechanisms such as altered physiological state, the slow growth rate of bacteria, the limited penetration of antibiotics through EPS, the increased horizontal transfer of resistance genes and mutations frequency, the accumulation of antibiotic-inactivating or modifying enzymes, alterations in gene expression, and activation of quorum sensing (QS) mechanisms [12][13].
In recent years the interest in the use of complexes for fighting biofilm associated infections has increased. These complexes exhibit multiple mechanisms of action at the microbial cell level, such as changes in microbial cell envelope permeability, reactive oxygen (ROS) or nitrogen (RNS) species release, DNA, membrane, proteins or EPS disruption, and enzyme inhibition to which an immunostimulatory effect upon the host is added [14][15][16][17][18][19][20]. These aspects assure therefore a better efficiency and a lower risk in selecting for antimicrobial resistance. Moreover, some complexes could block the QS process or inhibit the microbial adhesion [21].

2. Complexes with Antibiofilm Activity

One of the most promising approaches for the treatment of biofilm-associated infection is based on designing agents that exhibit multiple mechanisms of action.
So far, for antibiotics, the achievement of an anti-biofilm activity was reached either by modification of the conjugated moieties to the basic antimicrobial backbone or by a combinatory therapy [22][23][24].
By combining the special characteristic of transition metal ions with that of a proper organic scaffold, a suitable therapeutic agent can be obtained. The scientific literature reports a large diversity of species concerning both metal ions and ligands available for designing such effective anti-biofilm species ranging from simple to bulky ligands and acting as unidentate to multidentate species. A variety of complexes with anti-biofilm activity, ranging from species with known antibiotics or natural products to new synthetic ligands, mainly with low toxicity and chelating ability have been developed. The metallic ions in these species are essential cations such Cu(I,II) [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75], Co(II) [28][29][30][76][77][78][79][43][44][45][46][47][80], Mn(II,III) [81][82][83][53][54], Zn(II) [27][28][29][30][84][45][53][54][62][63][64][65][66][67][68][69][70][85][86], and Ni(II) [28][29][30][43][44][45][46][47][53][54][57][61][62][63][64][65][66][67][68][69][70][72] and those known to be less toxic, such as Pt(II) [87][57], Pd(II) [87][88][57], Au(I) [89][38], Ag(I) [90][89][36][38][87][91][92][93] and Hg(II) [90][89]. Some of the compounds thus assembled have the advantage of a positive charge and thus the ability to establish electrostatic interaction with negatively charged components of biofilm (polysaccharides, proteins and DNA), allowing them to exert an enhanced anti-biofilm activity. Also, the metal ions can extend their coordination on QS components, adhesins or the biofilm matrix, generating new mechanisms for biofilm destruction. Redox active metal ions can generate reactive inorganic molecules such as ROS or RNS that can also be involved in obtaining the desired anti-biofilm effect. In addition, the strategies based on such a compound’s incorporation in organic or inorganic carriers are currently under extensive development.

2.1. Complexes with Antibiotics

When the activity of antibiotics and antifungals was outclassed both by the emergence of resistance and by the reduced efficiency against biofilms, solutions were sought to overcome these problems. One of these solutions was provided by antibiotic complexation to biocations and especially to transition metal ions, which easily change their oxidation state and as a result can interact with target biomolecules involved in the destruction of the biofilm by redox processes.
Among bacteria, Pseudomonas aeruginosa represents an important nosocomial pathogen that is responsible for a large spectrum of infections, such as endocarditis, cystic fibrosis, burn, wound and urinary tract infections. Its pathogenicity is related to virulence factors such as biofilm formation as well as exotoxins, elastase, alginate and siderophores production [94]. The major limitation of therapy in chronic pulmonary infection is the P. aeruginosa biofilm formation in the lung, this being over 1000-fold more resistant to antimicrobials compared to planktonic bacteria [95]. As result, complex [Cu(Hcip)(H2O)2]SO4·2H2O (1) (Hcip: ciprofloxacin-a fluoroquinolone antibiotic) was studied as anti-biofilm species able to provide a high concentration of Hcip in the lungs. [25]. Besides structure determination for (1·EtOH), another study demonstrated that at sub-minimum inhibitory concentration (MIC), this complex exhibits a significant reduction in motility, biofilm formation, alginate, violacein and pyocyanin production and sensitivity to H2O2 in a concentration dependent manner [26]. Considering the biological effects of complex (1) and its inhibitory activity on QS at low concentrations, quantified through the expression of QS genes lasI and lasR, this may be used as an effective approach in the management of infections caused by this microorganism.
Complex {[ZnCl2(fcz)2]·2C2H5OH}n (2) (fcz: fluconazole-a triazole antifungal) showed both strong inhibition of C. albicans clinical isolates biofilm formation at subinhibitory concentration and the ability to reduce its adherence to human non-small cell lung cancer A549 cells in vitro.
Compound [Mn(H2O)6]0.5[Mn(smx)3] (3) (smx: sulfamethoxazole–an antibiotic from the second generation of sulfonamides) was fully characterized by single crystal X-ray diffraction and proved to be an inhibitor of both the planktonic and biofilm embedded Staphylococcus aureus strain [81]. Complexes of Hg(II), Cu(II), Cd(II) and Ag(I) with this ligand were reported as anti-biofilm inhibitors for E. coli [90], while its species with Au(I), Cu(II), Ag(I), Hg(II) and Cd(II) were found to be active against biofilm produced by Mycobacterium abscessus, M. fortuitum, and M. massiliense strains, the most active being [Au(smx)(PPh3)] (4) (Ph: phenyl) species for all tested strains [89].

2.2. Complexes with Heterocyclic Derivatives

During the last decades, fused heterocycles bearing 1,2,4-triazolo[1,5-a]pyrimidine scaffold aroused the pharmaceutical interest due to their resemblance with purine bases. As result, several complexes of Co(II), Ni(II), Cu(II), Zn(II) with such ligands were developed and tested on as anti-biofilm species. Among these, the series of complexes of type [MpmtpX2] (pmtp: 5-phenyl-7-methyl-1,2,4-triazolo[1,5-a]pyrimidine; X: Cl [28], CH3COO [29] and ClO4 [30] were tested on a wide range of microorganisms such as Gram negative (E. coli, K. pneumoniae, P. aeruginosa) and Gram positive (S. aureus, B. subtilis) bacterial strains, as well as the C. albicans fungal strain. A broad spectrum of anti-biofilm activity was demonstrated by all Cu(II) species [Cu2(pmtp)2Cl4(OH2)2] (5), [Cu(pmtp)(CH3COO)2]·0.5H2O (6) and [Cu(pmtp)(OH2)3](ClO4)·3H2O (7) from this series at subinhibitory concentrations, including MRSA and other clinical isolates [81][90][89]. In addition, (6) and (7) also induce a decrease in the DNA content of the cells found in the G0/G1 phase for the human colon adenocarcinoma cell line (HT 29), revealing their anti-proliferative potential [29][30].
Complex bearing 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) [Co(dmtp)2Cl2] (8) also exhibited a broad spectrum of anti-biofilm activity, being tested on the same strains [76]. Moreover, complexes with mixed ligands [Cu(bpy/phen)(dmtp)2(OH2)](ClO4)2·dmtp (9/10) proved to exhibit a stronger antimicrobial and anti-biofilm effect against the Gram-positive strains, including MRSA. In addition, compounds display an antiproliferative effect on murine melanoma (B16 cells); low toxicity on normal (BJ) cells, do not affect the membrane integrity and behave as metallonucleases [31].
The imidazole and its derivatives were also studied as ligands because of the ring presence in the protein structure as a part of histidine residues. Among these, [Mn(Him)6]Cl2·2H2O (11) (Him: imidazole) inhibits the E. coli biofilm [82] while [Cu2(acr)4(Hbzim/Me2bzim)2] (12/13) (Hacr: acrylic acid, Hbzim: benzimidazole, Me2bzim: 5,6-dimethylbenzimidazole) exhibited anti-biofilm activity on a wide range of bacteria (E. coli, S. aureus, B. subtilis, E. faecium) as well as C. albicans, activity complemented for (12) by an antiproliferative effect on the colon adenocarcinoma (HT29) cell line [32][33].
Several complexes of type [Cu(cbl)(PPh3)2X] (17) (X: Cl, Br, I) with β-carboline (cbl) at sub-MIC concentration interfered significantly with the QS regulated functions in Chromobacterium violaceum (violacein), P. aeruginosa (elastase, pyocyanin and alginate production) and S. marcescens (prodigiosin). Aside from the inhibitory effect on the EPS production and swarming motility, these complexes also demonstrated potent broad-spectrum inhibition of biofilm formed by P. aeruginosa, E. coli, C. violaceum, S. marcescens, K. pneumoniae and L. monocytogenes [35]

2.3. Complexes with Schiff Bases

In recent years, researchers have drawn significant attention toward Schiff bases and their metal complexes considering their numerous applications in the biological field, such as their antiviral, antimicrobial, antimalarial, and antitumor properties. Furthermore, some of complexes exhibit a good anti-biofilm activity besides the antimicrobial one against planktonic bacteria.
A series of complexes with Schiff bases bearing 1,2,4-triazole moiety of type [M(BS1)(X)]·nH2O (32) (M: Co, Ni, Cu, Zn; HBS1: 2-[(E)-(1H-1,2,4-triazol-3-ylimino)methyl phenol, X: Cl [43], CH3COO [44], ClO4 [45]) behave as good antimicrobials against both planktonic or adherent cells of a plethora of pathogenic microorganisms (E. coli, K. pneumoniae, S. aureus, B. subtilis, C. albicans) both on susceptible and resistant strains. The best activity was achieved for Cu(II) and Zn(II) species and, moreover, Cu(II) complexes of the series also exhibited a promising antiproliferative activity on human laryngeal carcinoma (HEp 2) and HT 29 cell lines.
Complexes [M(BS2)2(OH2)n] (33) (M: Co(II), Ni(II), Cu(II), HBS2: Schiff bases derived from cefotaxime/ceftazidime and salicylaldehyde, n = 2, 0) were studied as anti-biofilm species against E. coli, K. pneumoniae, S. aureus, and B. subtilis, the most active being Cu(II) compounds against E. coli and P. aeruginosa biofilms at sub-MIC concentrations [46][47]. The compounds [Ca(HBS3)(OH2)4]Cl2·4H2O (34) and [Cu{Ca(BS3)(OH2)2}2]Cl4·H2O (35) (HBS3: 2-hydroxy-8-methyl-tricyclo[7.3.1.02.7]tridec-13-N-4′(benzo-15-crown-5-ether)-imine) exhibited superior anti-biofilm activity compared to that of the ligand against several bacterial strains and C. albicans [48].

2.4. Complexes with Biguanide Derivatives

From the perspective of anti-biofilm activity, the complexes with biguanide derivatives have also shown promising potential. The biguanides are valuable ligands that can coordinate in neutral, anionic or cationic form. Due to their chelate coordination through the imide groups they form stable complexes with transition metal ions as neutral or anionic species [96].
The metformin (N,N′-dimethylbiguanide, Hdmbg) compound used for type II diabetes treatment by decreasing the glucose release from the hepatic tissue is also the best known of these derivatives as complex formatters [97]. Furthermore, the dmbg moiety incorporated into a polymeric material was used as an efficient catheter coating that prevented the development of S. aureus and E. coli biofilms [98], while a novel nano-system based on a polybiguanide moiety was recently developed as a biocompatible and effective inhibitor of MRSA biofilms both in vitro and in vivo [99].
This anti-biofilm potential of biguanides motivated the research for the design of complexes with such ligands. Among these, complexes [M(Hdmbg)2]X2 (41) (M: Mn(II), Ni(II), Cu(II), Zn(II); X: CH3COO [53], and ClO4 [54]) with this ligand demonstrated the ability to inhibit S. aureus and P aeruginosa biofilm development on inert substratum, the most active being Cu(II) and Zn(II) complexes. Moreover, all complexes exhibited very low cytotoxicity levels on human cervical cancer (HeLa) cells.

2.5. Complexes with Macrocyclic Ligands

A series of complexes with macrocycle (mc) ligands [M(mc1/mc2)Cl2]·nH2O (50/51) (M: Ni, Cu, Zn; mc1: 1,3,5,8,11-pentaazacyclotridecane-3-yl-(pyrid-3-yl)-methanone; mc2: (4,5,11,12)-bisphenylen-1,3,6,8,10,13-hexaazacyclotetradecan-bis(pyrid-3-yl)methanone) synthesized by the template condensation were screened for anti-biofilm activity on both susceptible and resistant strains of P. aeruginosa, E. coli, K. pneumoniae, S. aureus, B. subtilis and C. albicans, and proved to be strong inhibitors in most cases at sub-MIC concentrations, especially the Cu(II) species. These species also exhibited antiproliferative activity on HEp 2 cells by inducing the cellular cycle arrest in the G2/M phase [62][63].
The complex [Cu(mc3)]Cl2 (52) (mc3: macrocycle synthesised by the condensation reaction between substituted carbohydrazone and thiosemicarbazide) was found to be able to disrupt the biofilm produced by MRSA [64] while the antibiofilm activity of EDTA-based phenylene macrocycle (edtaod) on L. monocytogenes, P. aeruginosa, S. typhimurium and S. aureus was enhanced by its complexation with Cu(II) and Fe(III), activity that is similar and closely related with the molecular volume of EDTA complexes [65].
Moreover, a series of complexes with bismacrocycle (bmc) ligands [M2(bmc1)](CH3COO)4 nH2O (53) (M: Ni, Cu, Zn; bmc1: 1,2-bis(N,N-1,3,6,9,12-pentaazacyclotridecane)-benzene) were designed as antimicrobials and Zn(II) complex exhibit ability to inhibit the S. aureus, B. subtilis, E. faecalis, K. pneumoniae, E. coli, E. cloacae, P. aeruginosa and C. krusei adherence on inert substratum [66].

2.6. Complexes with Miscellaneous Ligands

A good inhibition against S. marcescens and C. albicans biofilm was evidenced for polymeric complex (H2apa)2[Mn(C2O4)2]·H2O (58) (Hapa: 2-aminopyridine-4-carboxylic acid) based on an oxalate linker associated with a lysozyme activity of the compound [100], while (Hmbzim)3[Fe(C2O4)3].3H2O (mbzim: 5-methylbenzimidazole) disrupted the biofilm only in case of C. albicans [101].
The metal-organic framework (MOF) {[Co2(bptc)(DMF)2(H2O)]DMF·H2O}n (59) (H4bptc: 3,3,5,5-biphenyltetracarboxylate) was prepared and structurally characterized. The results of the violet crystal staining experiment showed that the new compound significantly inhibited the formation of the S. aureus biofilm in vitro [102].
The complex [Cu(cur)2] (60) (cur: curcumin) inhibited biofilm formation in the case of S. aureus and significantly repressed the expression of lasI and lasR genes, demonstrating its QS inhibitory effect [71].
The assays performed on E. coli, P. multocida and S. aureus with complex [Ni(tea)2]·2bza (61) (tea: triethanolamine, Hbza: benzoic acid) indicated moderate to very good anti-biofilm activity [72].
The Cu(II) complexes of 1/2/3-(bromophenyl)-3-(1,7,8,9-tetramethyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl)thiourea derivatives exhibited good biofilm inhibitory activity on S. epidermidis [73], while [Cu2(S-et/bu-thiosal)4(H2O)2] (62/63) (S-et-thiosal: S-ethyl derivative of thiosalicylic acid; S-bu-thiosal: S-butyl derivative of thiosalicylic acid) exhibited anti-biofilm activity on a clinical S. aureus isolate similarly or even better than doxycycline used as positive control [74]. A similar activity was evidenced for Cu(II) complexes with 3-(trifluoromethyl)phenylthiourea derivatives, activity related to the inhibition of DNA gyrase and topoisomerase IV from S. aureus [75].
The compound [Co(edtp)Cl)](NO3)·H2O (64) (edtp: N,N,N’,N’-tetrakis(2-hydroxypropyl)ethylenediamine) exhibited moderate antithrombolytic activity and negligible cytotoxicity against bovine erythrocytes and in addition a very good bacterial biofilm inhibition (90%) against both B. subtilis and E. coli strains [80].
Moreover, the complex with mixed ligands [Zn(tsa)(tmeda)]2 (65) (Htsa: thiosalicylic acid; tmeda: N,N,N′,N′-tetramethylethylenediamine) is very active on the old biofilms of S. aureus, as indicated in the studies performed by confocal laser scanning microscopy which revealed its bactericidal activities, possibly by membrane alterations, as demonstrated by the propidium iodide (PI) uptake [85].
Complexes [Zn(bedtcm/imdtcm)2] (66/67) (bedtcm: N-(benzyl)-(ethyl)-dithio carbamate, imdtcm: N-(4-isopropyl-benzyl)-(4-methoxy-benzyl)-dithiocarbamate) exhibited anti-biofilm activity against both methicillin susceptible and resistant S. aureus [86], while [Ag(aptes)2NO3] (68) (aptes: 3-aminopropyltriethoxysilane) showed pronounced antibacterial effects against P. mirabilis isolated from patients with urinary tract infections, and exhibited a clear decrease in the ability of this bacteria to form biofilms at MIC concentration [93].
There are few reports concerning the anti-biofilm activity of some multidentate ligands bearing carboxylate/thiocarboxylate, hydroxy or amino groups. The good activity reported for species bearing sulfur as donor atoms opens promising leads that will likely boost future research in the field.
The anti-biofilm activity of complexes together with identified mechanisms of action is presented in Figure 1.
Figure 1. Anti-biofilm activity of complexes: 1-antimicrobial activity, 2-adherence inhibition, 3-QS inhibition and 4-biofilm destruction through ROS or NOS generation.

2.7. Materials as Carriers for Metal Ions or Complexes with Anti-Biofilm Activity

In order to overcome the problems associated with the use of antibiotics, some polymer species complexed with proper metal ions or loaded with biological active complexes as well as nanomaterials with anti-biofilm properties and biocompatibility/environmental safety have also been developed. Several dendrimers and polymers appropriately modified with coordinative groups able to chelate metal ions were designed for this purpose. Moreover, several attempts were made for the complexes’ incorporation into organic or inorganic matrices.

Dendrimers are branched three-dimensional macromolecules based on a nitrogen, phosphorus and silicone backbone, and carry groups able to coordinate metallic ions, properties that afford applications as metal ion carriers for anti-biofilm purposes. A proper selection of dendritic scaffold, generation type and nature of donor atom can provide a potent system that can overcome the limitations of traditional therapies with antibiotics [103]. As result, a second-generation poly(propylene imine) dendrimer modified with acridine and loaded with Cu(II) was developed first as an antimicrobial with low cytotoxicity against the human epithelial type 2 (HEp-2) cell line. Afterwards, a cotton fabric modified with this dendrimer was proved to exhibit anti-biofilm activity against B. cereus and P. aeruginosa strains, and no cytotoxicity on the HEp-2 cell line [104].
Another dendrimer from first generation of polyamidoamine (PAMAM) functionalised with 1,8-naphthalimide moiety was loaded with Cu(II) and attached to the cotton surface. The study showed that this material prevented the biofilm formation in the case of B. subtilis, B. cereus and A. johnsonii, the best effect being observed for the last strain [105]. Furthermore, a material based on a second generation PAMAM dendrimer modified with 4-(N,N-dimethylaminoethyloxy)-1,8-naphthalimide and conjugated with cis-Cu(NO3)2 moiety was developed and deposited on cotton fabric. The obtained composite exhibits inhibitory activity against B. cereus, P. aeruginosa and C. lipolytica biofilms [106]. On the other hand, a water-soluble carbosilane dendrimer, decorated with iminopyridine groups and conjugated with Cu(OH2)(ONO2)2 moiety (69), was developed as a potent species against both planktonic and biofilm embedded S. aureus and E. coli cells [107].
Among the polymeric composites, those generated by [Cu(dttct)](CH3COO)2 (70) (dttct: dibenzo[e,k]-2,3,8,9-tetraphenyl-1,4,7,10-tetraaza-cyclododeca-1,3,7,9-tetraene) incorporation into poly(vinyl chloride) (PVC) exhibited the ability to generate nitric oxide by nitrite reduction, a process assisted by the ascorbic acid. It was observed that this composite controlled both the formation and dispersion of nitrifying bacteria biofilm [108].
A series of 2,6-pyridinedicarboxylate-based polyesters employing several diols with different aliphatic chains were synthesised and complexed with Cu(II) and Ag(I). The composites were tested for their antibacterial potential and were found to effectively resist P. aeruginosa attachment and colonization, the silver-based polymers being superior in comparison with their copper analogues [109].
Schiff-base ligands were grafted on a natural biopolymer of ε-poly-L-lysine functionalized mesoporous silica SBA-15 for the selective coordination of Ag(I). This nano-species (72) exhibited inhibitory effect on E. coli, S. aureus, M. tuberculosis and C. albicans. Besides killing the C. albicans cells, this system inhibited biofilm formation and eliminated preformed biofilms, with no development of resistance during continuous serial passaging. The antifungal activity is related to the disruption of bacterial cell membranes and increased levels of intracellular ROS. In mouse models of multidrug-resistant C. albicans infection, nano-species exhibited an efficient in vivo fungicidal efficacy superior to the antifungal drugs, amphotericin B and fluconazole. Moreover, treatment induced negligible toxicity against normal tissues [110].
Anti-biofilm agents based on Ga(III) or zinc Zn(II) complexed with protoporphyrin IX or mesoprotoporphyrin IX were found to be highly effective in the inhibition of both planktonic bacterial growth and biofilm formation. These complexes were incorporated in poly(ether urethane) (PEU) polymer films in order to obtain a system for their controlled sustained release by using poly(ethylene glycol) (PEG) as a pore-forming agent. All complex-loaded PEU films exhibited in vitro a ≥ 90% reduction of S. epidermidis and P. aeruginosa in both suspended and biofilm culture. Moreover, the cytotoxicity and endotoxin evaluation demonstrated no adverse responses, while in vivo studies further substantiated the anti-biofilm efficacy of these composites [111].
A composite material based on polylactic acid (PLA) fibres containing cobalt-based MOF [Co(mcim)4](NO3)2 (73) (mcim: 4-methyl-5-carboxyaldehyde-imidazole) was prepared by electrospinning PLA with a suspension of polyvinylpyrrolidone-stabilized of (73). MOF particles formed aggregates that, after being electrospun, became completely embedded inside of polymeric fibres, which inhibited t S. aureus biofilm [112].
The development of an effective treatment for MRSA infections is complicated by the fact that antibiotics can be degraded by β-lactamases, and the antibiotics cannot penetrate the full depth of biofilms. Considering the nanoparticle-based carriers’ ability to deliver antibiotics with better biofilm penetration, a platform for β-lactam antibiotics and β-lactamase inhibitors co-delivery based on metalcarbenicillin framework-coated mesoporous silica nanoparticles (MSN) was developed. Carbenicillin, a β-lactam antibiotic, was used as a ligand for Fe(III) in order to generate a metalcarbenicillin framework able to block the pores of the MSN. The study evidenced that this system achieved a better penetration in the depth of biofilms and exhibited an inhibitory effect on the MRSA biofilm both in vitro and in vivo [113].
Despite the current tendency to use drug delivery systems (DDSs) based on biocompatible and biodegradable matrices, the studies concerning the use of DDS for anti-biofilm species are rather few. The available studies are reporting Cu(II) or Ag(I) coordination to dendrimers or natural or synthetic polymers providing N as donor atoms or the incorporation of some complexes into polymeric (linear or branched) or silica matrices, or even in organic-inorganic composites.

3. Conclusions

One of the most promising leads for the design of new complexes with anti-biofilm activity are the redox active metal ions such Cu(II), Fe(III) and Mn(II) but the less-studied ones such VO(IV) and Ru(II) should be also considered. All of these ions have ROS or NOS generation as a common mechanism of action. The best anti-biofilm activity is achieved then these ions are combined with multidentate ligands, especially bearing N as donor atoms, assuring enhanced stability. Furthermore, the perchlorate anion that easily generates single crystals seems to enhance the anti-biofilm activity in complexes bearing neutral organic ligands. The most active compounds show an improved activity after incorporation in organic, inorganic or composite matrices. The majority of the current literature refers to the in vitro study of the anti-biofilm activity of complexes, this explaining the paucity of novel anti-biofilm agents in medical practice. Thus, there is an urgent need for additional in vivo studies in this field in order to elucidate the safety, efficacy and toxicity of these species in order to develop new valuable drugs for the treatment of biofilm-associated infections.

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