Due to the emergence of multi-drug resistant strains, development of novel antibiotics has become a critical issue. One promising approach is the use of transition metals, since they exhibit rapid and significant toxicity, at low concentrations, in prokaryotic cells. Nevertheless, one main drawback of transition metals is their toxicity in eukaryotic cells. Here, we show that the barriers to use them as therapeutic agents could be mitigated by combining them with silver. We demonstrate that synergism of combinatorial treatments (Silver/transition metals, including Zn, Co, Cd, Ni, and Cu) increases up to 8-fold their antimicrobial effect, when compared to their individual effects, against E. coli and B. subtilis. We find that most combinatorial treatments exhibit synergistic antimicrobial effects at low/ non-toxic concentrations to human keratinocyte cells, blast and melanoma rat cell lines. Moreover, we show that silver/(Cu, Ni, and Zn) increase prokaryotic cell permeability at sub-inhibitory concentrations, demonstrating this to be a possible mechanism of the synergistic behavior. Together, these results suggest that these combinatorial treatments will play an important role in the future development of antimicrobial agents and treatments against infections. In specific, the cytotoxicity experiments show that the combinations have great potential in the treatment of topical infections.

IntroductionOne of the main issues in the medical field and clinical practice is the development of novel and effective treatments against infections caused by antibiotic-resistant bacteria. One avenue that has been approached to develop effective antimicrobials is the use of silver nanoparticles (Ag-NPs), since they have been found to exhibit an efficient and wide spectrum of antimicrobial properties. Among the main drawbacks of using Ag-NPs are their potential cytotoxicity against eukaryotic cells and the latent environmental toxicity of their synthesis methods. Therefore, diverse green synthesis methods, which involve the use of environmentally friendly plant extracts as reductive and capping agents, have become attractive to synthesize Ag-NPs that exhibit antimicrobial effects against resistant bacteria at concentrations below toxicity thresholds for eukaryotic cells.PurposeIn this study, we report a green one-pot synthesis method that uses Acacia rigidula extract as a reducing and capping agent, to produce Ag-NPs with applications as therapeutic agents to treat infections in vivo.Materials and methodsThe Ag-NPs were characterized using transmission electron microscopy (TEM), high-resolution TEM, selected area electron diffraction, energy-dispersive spectroscopy, ultraviolet–visible, and Fourier transform infrared.ResultsWe show that Ag-NPs are spherical with a narrow size distribution. The Ag-NPs show antimicrobial activities in vitro against Gram-negative (Escherichia coli, Pseudomonas aeruginosa, and a clinical multidrug-resistant strain of P. aeruginosa) and Gram-positive (Bacillus subtilis) bacteria. Moreover, antimicrobial effects of the Ag-NPs, against a resistant P. aeruginosa clinical strain, were tested in a murine skin infection model. The results demonstrate that the Ag-NPs reported in this work are capable of eradicating pathogenic resistant bacteria in an infection in vivo. In addition, skin, liver, and kidney damage profiles were monitored in the murine infection model, and the results demonstrate that Ag-NPs can be used safely as therapeutic agents in animal models.ConclusionTogether, these results suggest the potential use of Ag-NPs, synthesized by green chemistry methods, as therapeutic agents against infections caused by resistant and nonresistant strains.

Uncontrolled diabetes results in several metabolic alterations including hyperglycemia. Indeed, several preclinical and clinical studies have suggested that this condition may induce susceptibility and the development of more aggressive infectious diseases, especially those caused by some bacteria (including Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, among others) and viruses [such as coronavirus 2 (CoV2), Influenza A virus, Hepatitis B, etc.]. Although the precise mechanisms that link glycemia to the exacerbated infections remain elusive, hyperglycemia is known to induce a wide array of changes in the immune system activity, including alterations in: (i) the microenvironment of immune cells (e.g., pH, blood viscosity and other biochemical parameters); (ii) the supply of energy to infectious bacteria; (iii) the inflammatory response; and (iv) oxidative stress as a result of bacterial proliferative metabolism. Consistent with this evidence, some bacterial infections are typical (and/or have a worse prognosis) in patients with hypercaloric diets and a stressful lifestyle (conditions that promote hyperglycemic episodes). On this basis, the present review is particularly focused on: (i) the role of diabetes in the development of some bacterial and viral infections by analyzing preclinical and clinical findings; (ii) discussing the possible mechanisms by which hyperglycemia may increase the susceptibility for developing infections; and (iii) further understanding the impact of hyperglycemia on the immune system.

Bacterial exopolysaccharides (EPSs) are biomolecules secreted in the extracellular space and have diverse biological functionalities, such as environmental protection, surface adherence, and cellular interactions. EPSs have been found to be biocompatible and eco-friendly, therefore making them suitable for applications in many areas of study and various industrial products. Recently, synthesis and stabilization of metal nanoparticles have been of interest because their usefulness for many biomedical applications, such as antimicrobials, anticancer drugs, antioxidants, drug delivery systems, chemical sensors, contrast agents, and as catalysts. In this context, bacterial EPSs have been explored as agents to aid in a greener production of a myriad of metal nanoparticles, since they have the ability to reduce metal ions to form nanoparticles and stabilize them acting as capping agents. In addition, by incorporating EPS to the metal nanoparticles, the EPS confers them biocompatibility. Thus, the present review describes the main bacterial EPS utilized in the synthesis and stabilization of metal nanoparticles, the mechanisms involved in this process, and the different applications of these nanoparticles, emphasizing in their biomedical applications.

Due to the recent emergence of multi-drug resistant strains, the development of novel antimicrobial agents has become a critical issue. The use of micronutrient transition metals is a promising approach to overcome this problem since these compounds exhibit significant toxicity at low concentrations in prokaryotic cells. In this work, we demonstrate that at concentrations lower than their minimal inhibitory concentrations and in combination with different antibiotics, it is possible to mitigate the barriers to employ metallic micronutrients as therapeutic agents. Here, we show that when administered as a combinatorial treatment, Cu 2+ , Zn 2+ , Co 2+ , Cd 2+ , and Ni 2+ increase susceptibility of Escherichia coli and Staphylococcus aureus to ampicillin and kanamycin. Furthermore, ampicillin-resistant E. coli is re-sensitized to ampicillin when the ampicillin is administered in combination with Cu 2+ , Cd 2+ , or Ni 2 . Similarly, Cu 2+ , Zn 2+ , or Cd 2+ re-sensitize kanamycin-resistant E. coli and S. aureus to kanamycin when administered in a combinatorial treatment with those transition metals. Here, we demonstrate that for both susceptible and resistant bacteria, transition-metal micronutrients, and antibiotics interact synergistically in combinatorial treatments and exhibit increased effects when compared to the treatment with the antibiotic alone. Moreover, in vitro and in vivo assays, using a murine topical infection model, showed no toxicological effects of either treatment at the administered concentrations. Lastly, we show that combinatorial treatments can clear a murine topical infection caused by an antibiotic-resistant strain. Altogether, these results suggest that antibiotic-metallic micronutrient combinatorial treatments will play an important role in future developments of antimicrobial agents and treatments against infections caused by both susceptible and resistant strains.

Finding novel antibiotics and antimicrobial materials has become of great importance to modern society due to the alarming increase in the development of multidrug resistance in various bacterial strains. This problem is even more complex when infections involve bacterial strains in stationary metabolic states, since most of the antibiotics found in the market do not have an effect on bacteria in dormant metabolic states. A promising field to aid in the solution of this problem is nanotechnology, since it offers a wide avenue for the development of potential therapeutics, specifically the use of silver metal nanoparticles. Silver nanoparticles have proven to be highly effective antimicrobial agents and excellent candidates to be engineered and designed into clever delivery systems, taking advantage of their rapid and potent toxicity on prokaryotic cells at low concentrations. Metal nanoparticles are most commonly synthetized through one or a series of redox chemical reactions using powerful but environmentally toxic-reducing agents. Therefore, in this work, we propose a biosynthesis method that allows the production of nanoparticles, with homogenous shapes and narrow size distributions, through an environmentally friendly technique that does not produce toxic residues. Here, silver nanoparticles were produced from silver salt (AgNO3) using three different growth culture media residues from E. coli top 10. The three different culture media residues used included LB, LBN, and LBE; all of them displaying a different chemical and nutrient composition. Here, after characterization of the different silver nanoparticles produced with the different media, we demonstrated that the LB culture-conditioned media was the most suitable to produce them since they displayed the most narrow size distribution, with an average 10.6 nm in diameter, a relatively low standard deviation of 5.5 nm, and a narrow UV-vis spectrum absorption peak at 420 nm. The other methods presented larger nanoparticle sizes and broader size distributions. Furthermore, nanoparticles produced with LB Lennox were found to be, at very low concentrations, effective antimicrobial agent against E. coli top 10 at stationary phase. Therefore, these results seem to contribute knowledge linked to the production of antimicrobial nanoparticles (Ag-NPs) through green synthesis and represent a platform to treat infections caused by nongrowing bacteria.

Introduction: Global increase in the consumption of antibiotics has induced selective stress on wild-type microorganisms, pushing them to adapt to conditions of higher antibiotic concentrations, and thus an increased variety of resistant bacterial strains have emerged. Metal nanoparticles synthesized by green methods have been studied and proposed as potential antimicrobial agents against both wild-type and antibiotic-resistant strains; in addition, exopolysaccharides have been used as capping agent of metal nanoparticles due to their biocompatibility, reducing biological risks in a wide variety of applications. Purpose: In this work, we use an exopolysaccharide, from Rhodotorula mucilaginosa UANL-001L, an autochthonous strain from the Mexican northeast, as a capping agent in the synthesis of Zn, and Ni, nanoparticle biopolymer biocomposites. Materials and methods: To physically and chemically characterize the synthesized biocomposites, FT-IR, UV-Vs, TEM, SAED and EDS analysis were carried out. Antimicrobial and antibiofilm biological activity were tested for the biocomposites against two resistant clinical strains, a Gram-positive Staphylococcus aureus , and a Gram-negative Pseudomonas aeruginosa . Antimicrobial activity was determined using a microdilution assay whereas antibiofilm activity was analyzed through crystal violet staining. Results: Biocomposites composed of exopolysaccharide capped Zn and Ni metal nanoparticles were synthesized through a green synthesis methodology. The average size of the Zn and Ni nanoparticles ranged between 8 and 26 nm, respectively. The Ni-EPS biocomposites showed antimicrobial and antibiofilm activity against resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa at 3 and 2 mg/mL, respectively. Moreover, Zn-EPS biocomposites showed antimicrobial activity against resistant Staphylococcus aureus at 1 mg/mL. Both biocomposites showed no toxicity, as renal function showed no differences between treatments and control in the in vivo assays with male rats tests in this study at a concentration of 24 mg/kg of body weight. Conclusion: The exopolysaccharide produced by Rhodotorula mucilaginosa UANL-001L is an excellent candidate as a capping agent in the synthesis of biopolymer-metal nanoparticle biocomposites. Both Ni and Zn-EPS biocomposites demonstrate to be potential contenders as novel antimicrobial agents against both Gram-negative and Gram-positive clinically relevant resistant bacterial strains. Moreover, Ni-EPS biocomposites also showed antibiofilm activity, which makes them an interesting material to be used in different applications to counterattack global health problems due to the emergence of resistant microorganisms.

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