Phage therapy: A novel approach against multidrug-resistant pathogens

Abstract

The rapid rise of multidrug-resistant (MDR) organisms has created a critical need for alternative treatment options. Phage therapy is gaining attention as an effective way to fight bacterial infections by using lytic bacteriophages to specifically target and kill harmful bacteria. This review discusses several phage therapeutic options and emphasizes new developments in phage biology. Phage treatment has proven to be successful against MDR bacteria, as evidenced by multiple human clinical trials that indicate favorable results in treating a range of diseases caused by these pathogens. Despite these promising results, challenges such as phage resistance, regulatory hurdles, and the need for standardized treatment protocols remain. To effectively combat MDR bacterial infections, future research must focus on enhancing phage effectiveness, guaranteeing safety for human usage and incorporating phage therapy into clinical practice.

Keywords: Antimicrobial resistance; Bacterial disease; Bacteriophage; Drug-resistant pathogens; Phage therapy.

Fig. 1

Timeline of the development of phage therapy and antibiotics. The graph shows the milestones and key events throughout history that led to the development of both phages and antibiotics. The figure is reproduced with permission from (Gordillo et al. 2019)

Fig. 2

The bacteriolytic life cycle of phages. The figure is modified with permission from (Roach et al. 2017)

Fig. 3

Different approaches for the delivery of phage therapy to bacterial cells. The figure is reproduced with permission from (Gordillo et al. 2019)

Fig. 4

Diagram illustrating gram-positive bacterial cell lysis by exogenously applied endolysins. Endolysins cleave bonds in peptidoglycan and lead to lysis. Holins and endolysins cause cell lysis. The figure is reproduced with permission from (Roach et al. 2015)

Fig. 5

Diagram illustrating bacterial cells being attacked by phage-encoded proteins during lytic replication. Virion-associated peptidoglycan hydrolases are used by phages to puncture through the bacterial cell envelope. Depolymerases degrade polysaccharides that act as barriers to viral cell replication. The figure is reproduced with permission from (Roach et al. 2015)

Fig. 6

Different strategies used by bacteria to block phage adsorption. The figure is reproduced with permission from (Labrie et al. 2010). A At the first stage of adsorption, bacteriophages require specific receptors on bacteria for recognition and attachment. Step 1: Bacteria modify their cell surface receptors to become resistant to phage. Phages adapt and recognize these new receptors. Step 2: Bacteria also produce certain proteins that mask their cell surface receptors. Steps 3 and 4: For example, Staphylococcus aureus produces protein A, which reduces cell surface adsorption. B Phage adsorption can be blocked by the production of exopolysaccharides (EPS). To overcome this, phages can produce polysaccharide lyases or hydrolases to cleave EPS. C Phages have evolved to recognize polysaccharides such as the antigens O and K

Fig. 7

Pharmacodynamics explain the impact of the phage on the body, and the pharmacokinetics of the phage explain the impact of the body on the phage. The pharmacodynamics of phage therapy can explain the ability of individual phage particles to kill individual bacteria, while the pharmacokinetics of phage therapy can help us to understand the number of phage titers that are sufficient to effectively target bacteria. The figure is modified with permission from Dąbrowska and Abedon (2019)

Fig. 8

Factors affecting phage pharmacokinetics and pharmacodynamics. Factors such as phage administration and immune responses by host cells can affect the pharmacokinetics of phage therapy, while host range and resistance can affect the pharmacodynamics of the therapy. The figure is reproduced with permission from Dąbrowska and Abedon (2019)

Fig. 9

Human phage therapy trials and the range of target sites and infections. The figure is reproduced with permission from (Romero et al. 2019)

Fig. 10

Intrinsic and extrinsic factors affecting phage therapy. The figure is reproduced with permission from Oliveira et al. (2018)