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Inorganic compounds

Inorganic compounds, as anti-infectious agents, have the major advantage of a better versatility as they are usually more stable than the organic bioactive substances. Smaller and diversified, with excellent possibilities of doping, conjugating, and combining in new superior and exciting composites, they include among them one of the most studied and used bactericidal material from the new wave, whose behavior had been known and exploited for centuries—silver.

The simple addition of some inorganic salts or ions or their conjugation or administration as doping agents can ensure or enhance the antimicrobial properties needed to prevent infections associated with scaffolding, wound dressing treatments, or device implantation. Often times, their discharge is associated to standard antibiotics and or other drugs with anti-pathogenic activity, either through simple physical mixture or through chemical conjugation (Pallavicini et al., 2014).

Bioactive ions are employed in different organic-inorganic systems to improve their anti-pathogenic characteristics (Ozdemir et al., 2013). Metal-enriched bioactive compounds, such as Schiff bases derived from triazole and oxovanadium (IV) complexes have attracted major interest for the special antibacterial and antifungal properties.

Chohan et al. (2010) subjected them to the agar well diffusion method against E. coli, Shigella flexenari, P. aeruginosa, Salmonella typhi, S. aureus, and B. subtilis. The tested fungal strains belong to the following species: Trichophyton longifucus, C. albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, and Candida glabrata, with impressive results (Chohan et al., 2010). Pyrazinamide, a strong anti-mycobacterium agent, was modified to achieve increased efficiency against resistant mycobacterium. Hence two complexes were synthesized by a team of researchers, conditioned by the interaction of the active compound with Co(III) and Zn(II) ions based on 2,20-bipyridine and 1,10-phenanthroline ligands. Two model bacteria, E. coli and Bacillus thuringiensis were selected to be subjected to the antibacterial activity test of the novel compounds, which were further appreciated as remarkably effective (Chinoforoshan et al., 2015). Ozdemir et al. (2013) had reported in a paper the impressive biological activity of nickel(II), palladium(II), and platinum(II) complexes with aromatic ligands.

The antibacterial properties of terpydines containing sulfur and complexed with rhuthenim(II) and rhodium(III) were evaluated, and attracted interest since their bioactivity was found to be superior to standard drugs against Proteus vulgaris, P. mirabilis, P. aeruginosa, and E. coli and also five plant pathogens (Curvularia lunata, Fusarium oxys- porum, Fusarium udum, Macrophomina phaseolina, and Rhizoctonia solani). Mercury(II) complexes with phosphine-phosphonium salts were also showing promising results related to the antibacterial properties manifested in vitro (Samiee et al., 2013). Patil et al. (2015) designed Co(II), Ni(II), and Cu(II) coumarin Schiff base complexes with: (1) antibacterial activity against: E. coli, P. aeruginosa, Klebsiella sp., Proteus sp., S. aureus, and Salmonella sp.; (2) antifungal activity against: Candida sp., Aspergillus niger, and Rhizopus sp.; and (3) anthelmintic activity against Pheretima posthuma. Complexes with rhodium, iridium (Rao et al., 2016), and ruthenium (Nyawade et al., 2015) were also obtained, with future prospects after the preliminary in vitro studies (Beloglazkina et al., 2015).

The cumulative effect of two metallic ions (zinc and cerium) was observed in a composite whose continuous phase consisted of a-zirconium. Similarly, the tested bacterial species were E. coli and S. aureus (Cai et al., 2012). A research team also led by Cai, further investigated the effect of copper and neodymium ions on a-zirconium phosphate for the same bacterial species, acknowledging the action mechanisms and the lower cytotoxicity of these materials (Cai et al., 2015).

Studies performed in 2014 reported the therapeutic effect of various antimicrobial agents with incorporated metal ions against Gram-negative anaerobes, associated with periodontitis and peri-implantitis. The procedures for zinc, boron, silver, copper, tin, and platinum ion incorporation into various ceramic/glass/polymer/metal systems were detailed and the results were reported to other research conclusions. Silver ions were found to be the most effective against P. gingivalis, Prevotela intermedia, and Aggregatibacter actinomycetemcomitans (Goudouri et al., 2014). Composite ovalbumin/polyacrylonitrilenanofibrous films were endowed antibacterial activity against E. coli and S. aureus by the addition of silver ions (Song et al., 2013).

A similar study thoroughly investigates the influence of Li+, Zn2+, and Ti4+ ions on MgO nanopowders obtained by sol-gel method. The study concluded that the nature of the doping ions is essential in designing new antibacterial since only the Li-doped MgO powder retrieved better results regarding the inhibition of E. coli growth (Rao et al., 2013). Copper substrates enriched with Al and N ions also act bactericidal against Gram-positive bacteria species and, as a plus, improve the oxidation resistance of the metal structure (An et al., 2015).

Silver ions containing stainless steel were determined to exhibit a large spectrum of bactericidal features, which were evaluated for E. coli cultures that have prolonged effects and a rate of inhibition close to absolute values (Chen et al., 2013). Stainless steel with a content of copper ions behaves similarly, as previously described in a study aiming to find a convenient pathway for E. coli implant-associated infection prevention (Nan and Yang, 2010). Silver could be also used as a doping agent for titanium dioxide nanotubes, with noteworthy effects on S. aureus (Hou et al., 2015).

An interesting material was obtained by Hanim et al. (2016). They developed a silver-doped zeolite, which is able to exchange antibacterial silver ions with the environment. This functionalized material was tested with promising result on E. coli and S. aureus (Hanim et al., 2016).

Nanosilver is probably the most frequently used nanomaterial to applications meant to inhibit the colonization of bacterial populations. Thus, it is commonly employed in various composites as doping agent, dispersed phase, or coatings (Rai et al., 2015; Duran et al., 2015). Versatile and practical, numerous types of nanoparticles could come in aid of preventing and treating pathogen infections in biomedical and biomedical-related applications, depending on the synthesis route, shape, size, and functionalization (Moritz and Geszke-Moritz, 2013).

Hanh et al. (2016) immobilized silver nanoparticles in polymer fabrics by an in situ method. Prepared by y-irradiation of an AgNO3 solution, the noble metal nanoparticles were destined to act as a bactericide against the species that most commonly infect sheet in clinics: S. aureus, K. pneumoniae, Acinetobacter spp., E. coli, Enterobacter spp., Proteus spp., P. aeruginosa, Provindencia spp., Streptococcus pneumoniae, and S. epidermidis. The fabrics were repeatedly washed and tested for the preservation of antibacterial properties. The incidence of S. aureus and K. pneumoniae was reduced up to 99%; other drug-resistant bacteria were reduced in significant percentages of over 95%, thus concluding that the nanosilver-impregnated sheet can be successfully used for the prevention of hospital-acquired infections (Hanh et al., 2016).

High interest is also attracted by other noble metal nanoparticles. Generally, precious metals are thought to possess antimicrobial activity. Various dosages of green synthesis gold nanoparticles have been tested to confirm the theory against E. coli, Enterobacter sp., S. aureus, K. pneumoniae, and P. aeruginosa. After the 24 h incubation period, the diameter of the inhibition zone was measured. Not surprisingly, the bacterial reduction was proportional to the colloid concentration, S. aureus cultures exhibiting the most important inhibition (Rajan et al., 2015). Previously, a research team led by Muthuvel evaluated the antibacterial properties of gold nanoparticles obtained in the presence of reducing agent from Solanum nigrum leaf extract against significant Gram-positive bacteria (Staphylococcus saprophyticus and B. subtilis) and Gram-negative bacteria (E. coli and P. aeruginosa) with excellent results (Muthuvel et al., 2014).

Often, implants and medical device surfaces need to be both bacterial proof and biocompatible, inhibiting the coagulation and adherence of blood cells on their walls. A novel gold nanoparticles/sulfonated chitosan coating with biomedical applications has been developed; the biological testing included investigations on E. coli cultures. It was concluded that the bioactive nanosilver in the coating inhibited bacterial motility and prevented the adherence of pathogenic bacteria on its surface (Ehmann et al., 2015).

Recurrently, bactericidal tests are being performed on both silver nanoparticle and gold nanoparticle systems, for a better understanding of their action mechanisms and to obtain a broader image of their behavior by comparing results. Polydispersed green synthesis allowed the production of spherical Ag and cubic Au nanoparticles, which were tested on E. coli and S. aureus cultures. Their pronounced antibacterial effect was revealed by visually examining the inhibition areas; both type of nanoparticles proving to be powerful tools, which could improve the properties of medical devices, but as previously confirmed, E. coli manifested a higher tolerance to the exposure at every utilized dosage (Paul et al., 2016). Synergistic action of Au and Ag nanoparticles and natural compounds was also investigated. Park et al. (2016) tested resveratrol-AgNPs and resvera- trol-AuNPs against Gram-positive and Gram-negative bacteria, with the highest antibacterial effect activity manifested toward S. pneumonia strains.

The versatile features of copper and copper oxide nanoparticles allow their use in biomedical applications due to their capacity to inhibit and annihilate bacterial or fungal populations (Kruk et al., 2016; Raja Naika et al., 2015). One study reports the investigation of colloid copper nanoparticles against numerous strains of belonging to Staphylococcus genus, such as S. aureus NCTC 4163, S. aureus ATCC 25923, S. aureus ATCC 6538, S. aureus ATCC 29213, S. epidermidis ATCC 12228, S. epidermidis ATCC 35984, and 10 MRSA strains, and also some common strains of yeasts: C. albicans ATCC 10231, C. albicans ATCC 90028, and Candida parapsilosis ATCC 22019. The strong registered antagonistic effect toward the pathogenic strains was compared to the result of the team’s previous study mentioned for nanosilver (Kruk et al., 2016). Copper and zinc nanoparticles dispersed in carbon nanofibers were validated as solid support for the prevention of bacterial growth. Remarkable efficiency and durable effect was reported for E. coli and S. aureus (Ashfaq et al., 2016).

The antibacterial properties of copper oxide synthesized via a green route were investigated. The team selected Klebsiella aerogenes, Pseudomonas desmolyticum, E. coli, and S. aureus as representative pathogenic strains. K. aerogenes and E. coli were less sensitive to the action of copper oxide nanoparticles, even at the highest concentration, however, promising results were reported against other strains (Raja Naika et al., 2015). A composite for tissue regeneration including copper oxide nanoparticles synthesized in situ and chitosan was described as displaying good antibacterial behavior against E. coli and S. aureus (Farhoudian et al., 2016).

The combined effect of copper and copper nanoparticles was highlighted in a study in relation to the antibacterial properties of silica thin films doped with the respective nanoparticles. Apart from the cytotoxicity of the metal nanoparticles regarding E. coli, copper nanoparticles improved the bactericidal effect with their photocatalytic activity (Akhavan and Ghaderi, 2010).

Core-shell nanoparticles can act as antibacterial agents too. In a comparative study, it was shown that Ag-TiO2 and Ag-SiO2 can substantially inhibit E. coli and Saureus. The phenomenon according to which positively charged silver nanoparticles react easier with Gram-negative bacteria was also stated (Dhanalekshmi and Meena, 2014).

Over the last decade, various metal oxide nanoparticles were likewise designed and studied for their antibacterial properties. K. aerogenes, E. coli, P. desmolyticum, and S. aureus were found at agar well diffusion method to be sensitive and inhibited when put in contact with corundum (a-Al2O3) nanoparticles (Prashanth et al., 2015). E. coli was found to be susceptible to nickel oxide nanoparticles (Hasan et al., 2013). Moreover, in a 2016 study, nickel nanoparticles co-doped with boron and nitrogen were investigated to quantify their antimicrobial effect, which was first theorized after determining the photocatalytic properties. The bacteria killing capacity was determined for E. faecalis and E. coli and quantified around 95% (Fakhri et al., 2016). Another study centered on the photocatalytic effect of zinc oxide nanoparticles and their ability to kill bacterial entities, such as Streptococcus mutans (TavassoliHojati et al., 2013). Moreover, according to an ample in vivo study developed in mice, zinc oxide nanoparticles are able to induce oxidative stress response, the results being observed in vitro also. S. aureus, E. coli, and P. aeruginosa were incubated with nanoparticles at various concentrations. In the case of S. aureus, the cell membrane was disrupted by the oxidic nanoparticles. ROS production was expressed according to the result of the employed staining assay (Pati et al., 2014).

Functionalized titanium dioxide nanoparticles were revealed to enhance the antibacterial removal properties of fibrous membranes for water purification against S aureus, with results greater that 99.99%, due to the photocatalytic attributes (Daels et al., 2015) and the strengthened filtration performance (Li et al., 2015a). Different doping agents, such as silver and nitrogen (Ashkarran et al., 2014) or silver and zinc oxide (Roguska et al., 2015) completed and improved the photocatalytic and, overall, the antimicrobial activities of titanium oxide nanoparticles versus E. coli (Ashkarran et al., 2014) and nanotubes against S. epidermidis (Roguska et al., 2015). It was also established that nickel can actually enhance the antimicrobial activity of titanium dioxide nanoparticles against Gram-positive and Gram-negative bacteria. S. aureus,

B. subtilis, E. coli, and Salmonella abony suffered a considerable decrease in number of individuals. A more prominent effect was logged for the Gram-positive strains (Yadav et al., 2014). Moreover, nanocrystalline titanium with photocatalytically induced antibacterial effect was modified with iodine to enhance its activity in the visible spectrum (Lin et al., 2015).

 
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