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Strategies based on synthetic structures

Artificial active compounds were not the first type of bioactive substances humankind treated and then prevented infections with, but at the time of their first administrations, their effect had spectacularly positive outcomes. Although they were stronger, with a more radical behavior, some pathogen strains adapted and rendered them rather useless. These circumstances determined the scientists to pursue the design of novel and more efficient structures, and available approaches proved to be plenty, especially after the nanotechnology boom.

Organic compounds

Among the vast spectrum of organic compounds, there are some that naturally or after chemical modifications could be used in the prevention and treatment of various infections. Biochemists and medical engineers struggle to discover and innovate convenient methods of synthesizing and administrating these substances, which could apply for the particularities of each case.

The antibacterial and antibiofilm properties of polysaccharides (alginate, lamina- ran, fucoidan) and fatty oil extracted from Laurus nobilis, as well as the essential oils, were investigated by a team of researchers led by Chmit. Their anti-pathogenic behavior was evaluated against both Gram-positive and Gram-negative bacteria: S. aureus, Staphylococcus epidermidis, E. faecalis, E. coli, and P. aeruginosa. The microdiluted plant extracts were found to manifest adequate antibacterial activities against all five strains tested, but failed to decrease the biofilm mass. The most effective compound against biofilms was alginate, which even at low concentrations managed to reduce biofilm (Chmit et al., 2014). Natural extract polysaccharide with antioxidant properties from Nostoc commune also demonstrated strong antibacterial activity against S. aureus and E. coli (Quan et al., 2015).

Unmodified and sulfonated polysaccharides extracted from Pleurotu seryngii and Streptococcus thermophilus were employed in a research study to determine their antibacterial properties. Good results were reported against E. coli and S. aureus for every compound tested, even at small dosages. Listeria monocytogenes was more sensitive to sulfonated compounds (Li and Shah, 2014). Natural extract of polysaccharide origin from Taraxacum officinale was reported efficient against strains of E. coli, Bacillus subtilis, and S. aureus. The study in case concluded that the antibacterial efficacy of some polysaccharides can be exploited for both medical and food preservation purposes (Wang, 2014).

Salts, such as imidazolium, pyrrolidinium, and piperidinium were screened for antibacterial activity against B. subtilis, S. aureus, E. coli, and P. putida, with the best results reported being related to Gram-positive bacteria (Iwai et al., 2011). The antimicrobial manifestation of imidazilium salt based on acridine and silver oxide complexes was thoroughly investigated in another paper, with good result against A. baumannii and P. aeruginosa (He et al., 2015).

In an in vitro study, four starch derivatives (6-hydroxymethyltriazole-6-deoxy starch (HMTST), 6-bromomethyltriazole-6-deoxy starch (BMTST), 6-chloromethyl- triazole-6-deoxy starch (CMTST), and 6-carboxyltriazole-6-deoxy starch (CBTST)) were tested against E. coli and S. aureus. All polysaccharides exhibited antibacterial activities with a remarkable inhibitory index of 97% achieved for CBTST. All in all, the antibacterial activity decreased as follows: BTST > CMTST > BMTST > HMTST > starch, which is consistent with the idea that the groups that have a superior ability to withdraw electrons reveal a higher antibacterial behavior (Tan et al., 2016).

E. coli and S. aureus were also the focus of an inhibitory test of sulfur-containing flavonoids. Dithiocarbonic esters with flavonone backbone and their respective 1,3-dithiolium salts display promising inhibitory behavior against Gram-positive and Gram-negative bacteria, with better results registered for Gram-positive strains (Bahrin et al., 2014). Bioactive Mannich bases with heteroaromatic ring system of

Ganciclovir were also tested against E. coli, S. aureus, and B. subtilis, and the results were compared to parent sulfonamides (Joshi et al., 2013). Relevant data with regard to the antibacterial activity of organic bases of sulfur (Tehrani et al., 2015; Mondal et al., 2015), chloride (Pugachev et al., 2013), and ammonia (Fadda and El-Mekawy, 2013; Basilico et al., 2015; Tawfik et al., 2015) compounds was reported by more studies.

Benicasa et al. (2015) showed that Bac7(1-35) peptide that is high in proline exhibits a considerable antibacterial effect, which ensured protection against Salmonella typhimurium infection in mice. As it is characterized by a rapid clearance, they PEG- ilated it and subjected it to in vitro test to establish if the anti-pathogenicity is preserved and to quantify the effects. Two types of PEG-ilated Bac7(1-35) were tested, one of which was hydrolyzable and accounted for a superior activity, as it released a carboxymethyl derivative after its cleavage in the human plasma. An important aspect of the antibacterial mechanism is related to the compound’s capacity to internalize into cells without permeabilizing the membranes (Benicasa et al., 2015).

One of the most successful approaches is connected to the reactive oxygen species (ROS) production. A promising modulation of the ROS activity was achieved by Aiassa et al., in a study on the effect of в-cyclodextrin- and amino acid-complexed chloramphenicol toward S. aureus, E. coli, and P. aeruginosa. The antivirulent activity registered by the novel components, correlated with the protective effect due to cysteine and glycine measured in human leucocytes recommends these formulas as a potent and safer form of therapy (Aiassa et al., 2015).

ROS-based systems can also address fungal infections. Candida albicans cell apoptosis was managed by lycopene, which had a complex effect involving membrane depolarization, mitochondrial dysfunction, and G2/M cell cycle arrest. It was proven that lycopene can induce fungal cell apoptosis by overloading with Ca2+ the cytosol and the mitochondria. Moreover, the ROS production completes the inner cell attachment by triggering mitochondrial dysfunctions that result in the translocation and activation of pre- and apoptotic factors in the cytoplasm. These findings could enable further studies meant to develop a lycopene-based fungicide with no secondary effects against the body (Choi and Lee, 2015).

Curcumin, like lycopene, is a natural compound that has gained awareness due to its antibacterial activity. Conjugated with silver nanoparticles, curcumin can compete as one of the most prominent safe methods for the treatment of infectious agents such as E. coli, S. aureus, Salmonellas spp., and Fusarium spp. (El Khoury et al., 2015). Curcumin was further investigated for the evaluation of its multiple features: antibacterial, antioxidant, and anticancer activities (Xie et al., 2015). In this study, nano-curcumin was obtained by solution-enhanced dispersion via supercritical CO2 and tested against S. aureus and E. coli strains at the minimum inhibitory concentration (MIC). Better results were obtained against S. aureus; the antibacterial mechanism being explained by the fact that curcumin-based nanoparticles might be able to anchor on the surface of the cell walls, disrupting the membrane, penetrating inside, and breaking down the organelles structure (Xie et al., 2015).

Muhammad and Ahmed optimized the production of antibacterial metabolites from the thermophilic bacterial strain Aeribacillus pallidus. Sensitivity of Micrococcus lutes and S. aureus toward the novel compound was quantified; the most susceptible to the natural peptide was found to be S. aureus with a decrease of 52%, while in the second case the decrease was 45% (Muhammad and Ahmed, 2015).

Biocompatible silver nanoparticles doped with ultrashort peptide hydrogels represent another class of materials that can be used to eradicate or control infections. As a plus, they can be simultaneously used for wound dressing applications. Reithofer et al. (2014) designed a composite based on a matrix of Ac-LK6-NH2 with silver nanoparticles synthesized in situ. A bacterial growth inhibition assay was employed to determine its effect against E. coli, P. aeruginosa, and S. aureus (Reithofer et al., 2014).

Crucial in the prevention of nosocomial infections is the prohibition of infectious agents adhering to the surface of medical instruments, such as catheters and scalpels. One method of ensuring that the adhesion is avoided is to cover some instruments with a layer of rubber-derived oligomers of natural origin (cis-1,4-polyisoprene): PP04 with no quaternary ammonium (QA); MV067, one QA; PP06, three QA groups. The test was conducted on three of the most common bacteria—P. aeruginosa, S. epidermidis, and S. aureus. The effectiveness varied with the pathogenic species and the nature of the oligomer; the most prominent results were achieved for PP06, which ensured an adhesion decrease by 50%. Not surprisingly, the most resilient species was P. aeruginosa (Badawy et al., 2013).

P. aeruginosa inhibition was the subject of another in vitro study meant to evaluate the antibacterial activity of iron(III) and copper(II) complexes bearing 8-quinolinol with amino acid-mixed ligands. Thus, four bioactive metal complexes were synthesized with hydroxiquinoline and amino acids. Higher sensitivity toward these complexes was registered for P. aeruginosa; E. faecalis showed higher resilience to the organometallic compounds (Amolegbe et al., 2015).

Hermetia illucens was the source of extraction of a peptide—defensin-like peptide 4 (DLP4)—which was subjected to antibacterial tests. Multidrug-resistant bacterial species were employed in the study. E. coli (KCCM 11234), E. aerogenes (KCCM 12177), P. aeruginosa (KCCM 11328), MRSA (methicillin-resistant Staphylococcus aureus, clinically isolated), S. aureus (KCCM 40881, KCCM 12256), B. subtilis (KCCM 11316), and S. epidermidis (KCCM 35494). The present study concluded that the insect-isolated defensin is efficient strictly against Gram-positive bacteria, highlighting the remarkable behavior toward S. aureus (Park et al., 2015b). Cathelicidin LL-37 is another peptide synthesized from living organisms, which manifest promising infection eradication properties. Human cathelicidins, such as other cathelicidins from vertebrates act like host defense peptides, manifesting antimicrobial effect and alarming the immune system in cases of infections (Xhindoli et al., 2015).

Li et al. (2015b) reported the development of a novel antibacterial material by functionalization of grapheme oxide with polyethylene glycol and polyhexamethylene guanidine hydrochloride (GO-PEG-PHGC). Its properties were investigated by incubating some Gram-negative (E. coli) and Gram-positive (S. aureus) bacterial strains in a medium containing a dispersion of GO-PEF-PHGC. For comparison, cultures of both species were incubated in GO, GO-PEG, and GO-PHGC. Their activity was qualitatively evaluated by a biocidal kinetic test. The results indicate that the GO-PEF-PHGC manifest the strongest antimicrobial behavior compared to all the other systems of one or two components. Simple and cost-effective, the novel composite attracts significant clinical interest (Li et al., 2015b). On the same strains, authors tested the impact of a polymer coating prepared by thiol-yne click photopolymerization of 1-propargyl-3-alkyl-1,3- diazanyl-2,4-cyclopentadiene bromide ([PAIM]Br) and tetra(3-mercapto-propionate) pentaerythritol (PETMP) using the initiator 2,2-dimethoxy-2-phenylacetophenone (DMPA). The polymer films were deposited on glass samples. It was determined after the biological tests (dynamic shake method) that the crosslinked films possess remarkable antimicrobial properties against both Gram-positive and Gram-negative strains, properties that increased proportionally to the length of alkyl chains. S. aureus was found to be more sensitive to the antibacterial film activity than E. coli (Zhou et al., 2016). Antibacterial polymer coatings as a means to eradicate S. aureus was also employed in designing a silver nanoparticle-based system with superior properties. Silanes were used for improving the coatings, with promising results (Ali et al., 2015).

Some systems are specially designed to exhibit antimicrobial activity and to promote and ensure tissue regeneration. Such a scaffold was described by Xin et al. (2016), and it is based on a polypropylene fabric with passive and active components. The fabric was modified by grafting povidone and glycidyl methacrylate monomers and also guanidine polymers. The material was tested for cell adhesion with regard to two strains of representative Gram-positive and Gram-negative bacteria. The added components improved the antimicrobial performance, thus the scaffold presenting superior antifouling and antimicrobial properties (Xin et al., 2016). Also, the synergistic antibacterial effect of gentamicin-loaded chitosan/poly-co-glycolic acid-coated titanium nanotubes was demonstrated against a strain of the Gram-positive pathogen S. epidermidis in terms of proliferation and biofilm impeding (Kumeria et al., 2015).

Copaiba oil-loaded polylactic acid/polyvinylpyrrolidone (PLA/PVP) blow spun nanofibers for tissue reconstructions were found to exhibit antimicrobial action against S. aureus. Copaiba oil release tests were more promising for the samples with a higher content of PVP, since it allows a higher oil load. Nonetheless, a synergistic effect of the natural extract and PVP was observed in the experiment, strongly suggesting the use of this novel material in future biomedicine (Bonan et al., 2015). The antimicrobial effect of PVP is also supported by the antimicrobial behavior of povidone-iodine (PVP-I) proven against Porphyromonas gingivalis and Fusobacterium nucleatum biofilms (Hosaka et al., 2012).

Helicobacter pylori had gained resistance to common treatment especially due to the impressive arsenal of virulence factors and ability to develop biofilm. In an in vitro study, H. pylori biofilms were treated with an architecturally complex nanoparticle system of lipid polymer nanoparticles, low dosages of amoxicillin, pectin sulfate, and a mixture of rhamnolipid and phospholipids. A biofilm-inhibiting phenomenon was observed, as well as an inhibition of the plankton cells from adhering to a cultured cell line, the result being influenced by the dose and exposure time (Cai et al., 2015).

Polyetheretherketone (PEEK) is used in small orthopedic and dental restorations due to its favorable properties. However, sulfonated PEEK was believed to also exhibit an important degree of antibacterial behavior. The results of the in vitro evaluation of sulfonated PEEK match the ones of the in vivo on mice against S. aureus and E. coli. The obtained results demonstrated that bacterial mortality is proportional to the sulfur content of the PEEK network. However, sulfur is not cytocompatible, and a convenient balance should be found for the further investigation and use of this system in biomedical applications (Ouyang et al., 2015).

Curcumin-loaded chitosan/cellulose microcrystal films were found to manifest a fair synergistic antimicrobial action toward both bacteria and fungi. This behavior was qualitatively evaluated through zone inhibition method for some pathogenic yeast (C. albicans, C. parapsilosis) and bacteria (E. coli) (Bajpai et al., 2015).

One of the more exotic polymeric materials with bactericidal properties is the polymeric micellar nanoplatforms for Fenton reaction promotion. A Fenton reaction describes the conversion of a mild oxidant (H2O2) to a radical with higher reactivity and toxicity by ferrous ions. The polymeric system consists of a hydrogen peroxide-generating polymer— poly [(3-phenylprop-2-ene-1,1 -diyl)bis(oxy)bis(ethane-2,1 -diyl) diacrylate]-co-4,4'(trimethylene dipiperidine)-copoly (ethylene glycol), PCAE— and iron-containing ferrocene. Amphiphilic PCAE is able to form micellar structures that can encapsulate ferrocene in their hydrophobic core. The in vitro experiments were made on E. coli and P. aeruginosa and had positive results; the micellae both damage the cell membrane and determine the ROS formation. In vivo experiments developed on mice by injecting the obtained nanoplatforms increased the survival rate of infected mice and manifested no inflammatory response or tissue architecture alterations and manifested low tissue depositions, which were decreased in time (Park et al., 2016).

Interestingly, polymers can also be used as a means of observing better the late stages of an infection and to improve the therapy. One remarkable example of this kind can be found in an article written by Butov et al. (2015), which deals with the changes in morphology of the necrotic tissue resulted from tuberculosis infection. The in vivo study done on a group of 32 infected mice, demonstrated the effect of a treatment involving quercitin and polyvynilpirrolidone (QP). One clear limitation between the necrosis and the unaffected tissue was observed in the mice that were administered QP. The effect was enhanced in the mice that received same doses of QP and classic tuberculosis drugs (izoniazid and streptomycin). The simple administration of tuberculosis drugs led to the observation of adipose dystrophy, thus suggesting the positive synergistic effect of QP. The formation of connective tissue separating healthy and necrotic areas is believed also to prevent the dissemination of tuberculosis (Butov et al., 2015).

Amino acids, peptides, proteins, polymers, and organic salts are, as illustrated, intensely studied, especially for the prevention of violent and drug resilient infection. However, it is yet difficult to address the medical community with the discovery of compounds close to the idea of a “gold standard” in antibacterial organic chemistry since the goal of balancing adequate cytotoxicity, availability, and costs has not been achieved yet.

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