Comparison of phage therapy with antibiotic therapy

PropertyPhage therapyAntibiotic therapy
SpecificityPhages have a high degree of species and strain specificity as they only disrupt target bacteria. Therefore, ecologically important bacteria (e.g., intestinal microbiota) remain safe [46].Antibiotics often kill a broad spectrum of both gram-positive and gram-negative bacteria, including beneficial bacteria, which is increasingly viewed as undesirable for normal microbiota [47].
Mechanism of actionDuring the lytic infection cycle, phage attaches to the bacterial cell’s receptors, then delivers its genomic content inside the cell and undergoes replication through bacterial transcription, translation, and assembling process. After forming new phage particles, they leave the cytoplasfm through the lysis of bacteria. And this procedure is repeated as the escaped phages infect other bacterial cells [48].

Antibiotics act in the following ways:

  • Inhibit the synthesis of cell wall

  • Breakdown of cell membrane structure and function of the bacterial cell

  • Inhibit the function and structure of nucleic acids

  • Inhibition of synthesis of protein

  • Disturb key metabolic pathways of the bacterial cell [49].

Biofilm degradationThere has been great interest in using phage therapy to eliminate biofilms. This is caused by phages’ capacity to produce enzymes (depolymerases) that break down a biofilm’s extracellular polymer matrix. Notably, biofilm-forming bacteria do not shield cells from bacteriophage destruction by producing extracellular polysaccharide-based matrices [50].Multiple tolerance mechanisms in biofilms forming bacteria resistant to antibiotic treatment (therapy). Continuous administration of antibiotics results in the persistence of biofilm infections, which increases the risk of the emergence of antibiotic resistance (genetic resistance) [51].
Immune responsePhages may cause innate and adaptive immune cells to respond, which could affect the efficacy of phage therapy. When pathogen recognition receptors (PRR) identify DNA and RNA derived by phages, innate immune cells can be activated. Moreover, phages can induce Antibody production as they have immunogenic proteins [52].Antibiotics do not directly affect innate immune response but involve releasing pathogen-associated molecular patterns (PAMPs) in response to compromised bacterial cell walls. They do not induce antibody production [53].
Side effectsNo severe adverse effects have been reported against phage therapy, making it an attractive treatment against bacterial infections [54].Antibiotics have numerous side effects, including allergies, intestinal disorders, and disturbance in the nervous system, and also promote various secondary infections (yeast infections) [55].
Development of resistance

The following strategies allow bacteria to develop resistance to phages:

  • Preventing the phage from attachment to its surface by mutations in receptor protein (Y) is known as phage adsorption inhibition [56].

  • By inhibiting the injection of phage genome into the cell, known as injection blocking.

  • After phage genome injection into a host, bacterial endonucleases can recognize and eliminate foreign DNA, which results in phage inhibition, known as restriction-modification.

  • The virus is prevented from spreading when phage-infected cells eventually die before completing the lytic cycle, known as abortive infection.

  • Acquired resistance can also develop by selecting non-susceptible strains based on the clustered regularly interspaced short palindromic repeats (CRISPR) system [57].

Resistance to antibiotics develops in the following ways:

  • Efflux pumps, which excrete the antibiotic from the cell.

  • Antibiotics can deactivate through enzymes.

  • Bacteria can produce another protein to bypass the inhibited one, target bypass.

  • Modification in the antibiotic target sites.

  • Resistance also happens through reduced uptake of antibiotics.

  • Quorum sensing allows bacteria to transfer their antibiotic-resistance genes to other bacteria [58].

Potential to overcome resistanceBacterial strains that get resistant to phages are lower in fitness, so they could not survive more. Phages may also change; they can evolve to compete with bacteria that are resistant to them. Moreover, the development of Phage resistance may be completely avoided if phages are utilized in cocktails (consisting of different types of phages) [59].A regimen of two to three antibiotics can be used against resistant infections but can lead bacterial strains to MDR strains. Resistance to antibiotics may spread to other bacteria, and new antibiotics against resistant bacteria may take several years to develop [60].
DiscoveryNew phage isolation and selection are less time- and money-consuming processes [54].An effective antibiotic medicine development often costs millions of dollars and takes several years to produce, in addition to assessing potential toxicity [61].