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tavassolian F, chegini Z, kjoshbayan A, farahani A, shariati ع. Bacteriophages: A Promising Therapeutic Approach for Inhibition of Bacterial Infections. RJMS 2024; 31
URL: http://rjms.iums.ac.ir/article-1-8186-en.html
khomein university of medical sciences , arefshariati0111@gmail.com
Abstract:   (349 Views)
Nowadays, the most important problem in the treatment of bacterial infections is the appearance of drug-resistant bacteria and the scarce prospects of producing new antibiotics. In this regard, methicillin-resistant Staphylococcus aureus (MRSA) is an antibiotic-resistant agent that poses
a remarkable threat to health care by causing 19,000 deaths and a cost of $3–4 billion annually in the US. The number of cases influenced by Multidrug-resistant (MDR), Extensively drug resistant (XDR), and Pandrug-resistant (PDR) Gram-negative bacteria, such as Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, as well as MDR or XDR isolates of Mycobacterium tuberculosis, has been growing continuously in recent years. The limitation of current clinical options for confronting threats of infections caused by intricate pathogens has led to a critical problem that encourages researchers to discover new approaches to face the growing problem of drug-resistant bacteria.

To this end, scientists are using different antibacterial agents, such as bacteriophages (phages), for the inhibition of bacterial infection and the improvement of antibiotic efficacy. Phages are viruses that infect bacteria, and due to the huge increase in antibiotic resistance in recent years, there is renewed interest in revisiting the use of phages to treat bacterial infections. The practice of phage therapy, the application of phages to treat bacterial infections, has been around for approximately a century. Phage therapy relies on using lytic phages and purified phage lytic proteins for the treatment and lysis of bacteria at the site of infection.
The use of two or more phage mixtures with different host ranges in a single suspension as a bacteriophage cocktail is usually more effective for inhibiting bacterial infections. Phage cocktail causes a better reduction of bacterial density and improves phages’ efficiency, and in vitro studies have also shown that phage cocktail results in a higher reduction in bacterial infection. Additionally, polysaccharide depolymerase, a polysaccharide hydrolase encoded by phages, can specifically degrade the macromolecule carbohydrates of the host bacterial envelope. This enzyme helps the phage adsorb, invade, and disintegrate the host bacteria. Furthermore, phages generate peptidoglycan hydrolase enzymes, called Endolysins, at the end of the lytic cycle. They decompose peptidoglycan from the inside and assist in forming new progeny phages to release from the cell. Endolysins are always proposed as antibacterial agents because of their high specific activity and unique mode of action against bacteria. The activity of Endolysins is independent of antibiotic susceptibility patterns.
The combined use of phage and antibiotics also indicated promising effects for inhibition of MDR bacteria. The sub-lethal concentrations of conventional antibiotics, for example, ciprofloxacin, could lead to an increase in progeny production. Antibiotic treatments could enhance the release of progeny phages by shortening the lytic cycle and latent period. Thus, sub-lethal concentrations of antibiotics combined with phages can be used for the management of bacterial infections with high antibiotic resistance. In addition, combination therapy exerts various selection pressures that can mutually decrease phage and antibiotic resistance.
It’s noteworthy to mention that bacterial biofilm was introduced for the first time in 1987 as a community of microorganisms capable of binding to surfaces and forming an exopolysaccharide and extracellular matrix. Biofilms are communities of bacteria that are surrounded by a complex polysaccharide matrix (glycocalyx). They are highly resistant to antibiotics, making them a major challenge. The antibiotics are unable to penetrate the matrix, which makes biofilms between 10 to 1000 times more resistant to antibiotics compared to individual planktonic cells.  This has led to an increase in the prevalence of multi-drug resistant (MDR) strains of bacteria in recent years. Unfortunately, there are no fully effective antibiotics available to stop these bacteria. However, phages can be used to eradicate biofilms. They work by destroying the extracellular matrix of the biofilm, which increases the permeability of antibiotics into the inner layer of the biofilm. Phages also inhibit the formation of biofilm by stopping the quorum-sensing activity.
Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties, such as nanoparticles, enzymes, and natural products, can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, using bacteriophages to destroy biofilm has some drawbacks, like a limited range of hosts, high-density biofilm, subpopulation phage resistance in biofilm, and quorum sensing in biofilm, which stops phage infection. Therefore, phages not only kill MDR bacteria but also destroy their biofilm structure. To this end, recently published studies used phage therapy for the inhibition of different bacterial infections, such as wounds, urinary tract infections, and chronic cystic fibrosis infections.
Recently published studies have proposed phage therapy as a potential alternative against MDR urinary tract infections (UTI) because the resistance mechanism of phages differs from that of antibiotics and few side effects have been reported for them. Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis are the most common uropathogenic bacteria against which phage therapy has been used. Phages, in addition to lysing bacterial pathogens, can prevent the formation of biofilms. Besides, by inducing or producing polysaccharide depolymerase,
Phage can easily penetrate into the deeper layers of the biofilm and degrade it. Notably, phage therapy has shown good results in inhibiting multiple-species biofilm, and this may be an efficient weapon against catheter-associated UTI.

Additionally, wound infections kill a large number of patients worldwide each year. S. aureus, K. pneumoniae, A. baumannii, and P. aeruginosa are the most important colonizing pathogens of wounds that, with various virulence factors and an impaired immune system, cause extensive tissue damage and non-healing wounds. Furthermore, the septicemia caused by these pathogens increases the mortality rate due to wound infections. Because of the prevalence of antibiotic resistance in recent years, the use of antibiotics to inhibit these pathogens has been restricted, and the topical application of antibiotics to wound infections increases antibiotic resistance. The results of published studies showed that phages have an excellent ability to inhibit MDR bacterial pathogens and wound infections and accelerate wound healing.
Studies have demonstrated that phages can prevent septicemia, which arises due to wound colonization by different pathogens. Furthermore, phages have good stability in different environmental conditions. Also, based on the studies, they have negligible side effects, which may increase their potential to be used for patients with underlying diseases or unstable physiological conditions, because they are more tolerable for patients than the toxic antibiotics.
Finally, pulmonary infections involving P. aeruginosa are among the leading causes of the deterioration of the respiratory status of cystic fibrosis (CF) patients. The emergence of MDR strains in such populations, favored by iterative antibiotic cures, has led to an urgent need for new therapies. Among them, phage-based therapies deserve a focus.
In this regard, studies have shown that phages can be used as a preventive or curative treatment for P. aeruginosa lung infections. However, the preferred route of administration, the dose, the duration of treatment, co-treatment with antibiotics, and the choice of a single agent or of a host-adapted or preexisting cocktail are still unclear.
Therefore, as mentioned, phages have shown promising results for managing bacterial infections. However, phages have different host ranges in various studies, which limits their use because MDR bacteria are usually nosocomial bacteria that may have different origins, and the isolated phage may not be able to infect some of them. Also, isolation of specific phages may be time-consuming and unnecessary for the patient. Furthermore, phages have low stability in long-term storage, but it is possible to use them in different ways, such as liposomal capsules and lyophilization. Therefore, using phages along with antibiotics, natural substances that have antimicrobial properties, or biological bands that increase wound healing can increase the chances of successful treatment. It is noteworthy that, using phage cocktails and providing phage banks can also increase their chances of success, as this is less time-consuming to isolate them and covers a wider host range. However, determining the use of phages to do the least harm to humans, methods to boost their effect on bacterial pathogens, the best time for the treatment, and the route or dosage of the administration need further studies.
Collectively, recently published studies used phage therapy for the inhibition of different bacterial infections, such as wounds, urinary tract infections, and chronic cystic fibrosis infections. However, despite the positive use of phage therapy, various studies have reported phage-resistant strains, indicating that phage-host interactions are more complicated and need further research. Additionally, these investigations are limited, and further clinical trials are required to make this treatment widely available for human use.
Type of Study: review article | Subject: Microbiology

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