Nanotechnology as Novel Antimicrobials Bayan Farhan, Deema Al Zoubi, Leyan Omat, Maha Omar, Yasmeen Abu Sharar.

Nanotechnology as Novel Antimicrobials Rising antimicrobial resistance is decreasing the effectiveness of widely used antimicrobials[2,3]. Scientists have been investigating several methods for overcoming antimicrobial resistance, one of the most novel methods today is utilizing nanotechnology in developing antimicrobial nanomaterials and nano-sized drug carriers[3].

What is Nanotechnology? Nanotechnology is a technology that exploits the properties of compounds at the nano- scale (1-100nm). In nanotechnology, we are trying partially to imitate nature and to build things starting with atoms.

What is Nanotechnology? Nanoparticles can target a bacterial cell individually which increases the effectiveness of the antimicrobial agent and decreases resistance development against it. Some nanomaterials can also play the role of the antibiotic agent themselves[8].

Nanobiotics Nanobiotics are nanomaterials which either show antimicrobial activity by themselves or enhance the properties of existing antibiotics[8].

Advantages and disadvantages of Nanobiotics Antimicrobial NPs Free antimicrobial agents Advantage Targeted drug delivery via specific accumulation Disadvantage No specific accumulation Lowered side effects of chemical antimicrobials High side effects of chemical antimicrobials Low antimicrobial resistance High antimicrobial resistance Controlled drug release Usual pharmacokinetics of free drugs Broad therapeutic index Narrow therapeutic index Improved solubility Sometimes poor solubility Low immunosuppression Immunosuppression Low cost High cost Accumulation of intravenously injected nanomaterials in tissues and organs Absence of nanomaterials in the whole body High systemic exposure to locally administrated drugs Low systemic exposure to locally administrated drugs Nanotoxicity (lung, kidney, liver, brain, germ cell, metabolic, etc.) Absence of nanotoxicity Lack of characterization techniques that are not affected by NPs' properties Well-established characterization techniques

Advantages of nanoparticles in medicine Nano particles used in diagnosis and treatment of diseases like: cancer and bacterial infections especially after the presence of antibiotics resistance.

Types of nanoparticles There are many types of nanoparticles that we can use it in bacterial infection, like: 1. Ag NP. 2. Au NP. 3. ZnO NP. But Ag NPs have the most antibacterial effect against bacteria, viruses and eukaryotic microorganisms.

Mechanisms of action of Ag NPs 1. Ag NPs can attach to the surface of bacterial cell membrane and distrub its functions like: permeability. 2. They are able to penetrate the bacterial cell and interact with sulfur- and phosphorus- containing compounds such as DNA. 3. They affect bacterial signal transduction and inhibit bacterial growth.

Nanopollution It can float in air might easily penetrate animal and plant cells causing unknown effects because of the greater its surface area to volume ratio. Nanoparticles have high chemical reactivity and this results in increased production of reactive oxygen species including free radicals that is one of the primary mechanisms of nanoparticles toxicity

Klebsiella pneumonia Klebsiella is a type of Gram-negative bacteria. It causes different types of infections: -pneumonia -bloodstream infections - wound or surgical site infections - meningitis. They are normally found in the human intestines and human stool (feces).

Infections commonly occur in healthcare settings among sick patients whose care requires devices like ventilators or intravenous catheters, and patients who are taking long courses of certain antibiotics.  Klebsiella bacteria have developed antimicrobial resistance, most recently to the class of antibiotics known as carbapenems.

Nanoparticles in treating k-pneumonia infections : 1-Silver carbine complex (SCC23-LTP NPs) -a broad-spectrum antimicrobial agents -with low toxicity. (they accumulate in lungs after nebulization resulting in a controlled release) The silver carbene complexe (SCC NPs) were tested against different pathogens include Klebsiella pneumoniae and the results show that it was active against highly resistant bacterial strains.

2- Silver nanoparticles (Ag NPs ) Size: 43nm , dosage 30 mg/l used in many food and drug products due to its good antimicrobial properties. - Distrubt to the cell membrane and inhibit bacterial growth. The studies talked about the adsorption and toxicity of SNPs on bacterial species such as Klebsiella pneumoniae at different pH including acidic, neutral and alkaline . 

The Maximum adsorption and toxicity was at acidic pH =5 with 20 c temperature The minimum adsorption and toxicity was at basic pH= 9 with same temperature. The study shows that the bacterial species was decreased with increase in adsorption of SNPs.

3- nitric oxide nanoparticle (NO NPS ) Size:10-15 nm MIC =10 mg/ml in 24 hours -a broad-spectrum antimicrobial agents - Alteration of the bacterial membrane (nitrosation of protein thiols and the nitrosylation of metal centers) The studies found that the nitric oxide-releasing nanoparticle were active against many different strains of bacteria that were sensitive and resistant to most commonly used antibiotics including Klebsiella pneumoniae . (3)

Pseudomonas aeruginosa A gram negative bacteria . Multi drug resistant . The spectrum of diseases caused by this bacterium continues to expand from urinary tract infection to septicaemia, and endocarditis.

Effect of Nanoparticles on Pseudomonas aeruginosa:

1-Effect of silver nanoparticles on Pseudomonas aeruginosa:

Result shows the inhibition zone for all samples were of approximately 11.6 mm when the organism was tested against 10 μg of nanoparticles. The results were similar in MDR strains and the susceptible strains. Gentamicin showed a larger inhibition zone amongst susceptible strains but there was aslight reduction in the zone of inhibition among the MDR strains as compared to the Ag nanoparticles.

This shows that the Ag nanoparticles have antimicrobial activity against the P.aeruginosa strains .

2-Effect of zinc oxide nanoparticles on pseudomonas aeruginosa biofilm formation: What is zinc oxide ? Zinc oxide nanoparticles (ZnO NPs) are reported to possess anti-microbial activity. These particles significantly can reduce the skin infection, bacterial load and inflammation in mice .

ZnO nanoparticle-coated surfaces inhibit bacterial biofilm formation and increase antibiotic susceptibility. They showed hydroxyl radicals, originating from the coated surface had a main role in anti-biofilm activity, but its effect is less to remove pre- formed biofilm.

Nanoparticles in treating staphylococcus aureus infections : -Staphylococcus aureus is a gram positive bacteria, it’s a common cause of many diseases. -MRSA is a worldwide problem. -S.aureus bacteria able to produce biofilms if they were on biomaterial implants like catheters, artificial joints and heart valves that impede the entrance of antibiotics .

Study : Catheters were coated with MgF2 nanoparticles in a uniform layer on both sides of catheters. MgF2-coated catheters were investigated for their ability to reduce the formation of biofilms. - Also, they were shown to be relatively harmless to mammalian cells.

We conclude that the surface modification of catheters with MgF2 nanoparticles can prevent the colonization of bacteria and make the catheters sterilized while they are in our bodies.

Study : Supermagnetic iron oxide nanoparticles (SPIONs) was tested on biofilms of gentamicin-resistant staphylococcus aureus. The results show that SPIONs cause a significant increase in the percentage of dead S.aureus. that the SPOINs must be targeted and concentrated on the biofilm using an external magnetic field to give the maximum effect.

The particles size of nanoparticles should range from 14-18 nm, and because of their small sizes; they can penetrate into bacteria easily.

Study: In the study of the effect of silver carbine complexes (SCCs), they were tested against different strains of bacteria including MRSA. They used LTP and PEG-PLA as a delivery systems to encapsulate SCCs. SCCs complexes has shown antimicrobial activity against MRSA. In vivo studies on mice that have pneumonia, they was effective, they accumulate in lungs after nebulization resulting in a controlled release of SCCs at the site of infection, thereby minimizing the toxicity.

The concentrations at which these complexes are effective may decreased with the administration of consecutive doses. Also, these complexes are relatively have low toxicity to human cells which make them promising alternatives to antibiotics that have become ineffective as in case of MRSA.