An adjuvant is a substance added to drugs or vaccines to accelerate and enhance the action of the main component. The use of adjuvants for bacteriophages is intended to enhance their antimicrobial activity and/or block the development of resistance in target bacteria. To date, the use of adjuvants for bacteriophages remains poorly understood.

Perhaps the best-studied approach is to combine phage preparations with antibiotics, which provides a synergistic antimicrobial effect. Antibiotics have been found to enhance phage replication. For example, subinhibitory concentrations of cephalosporins increase phage production in Escherichia coli cells by 7-fold [1]. In phage-infected Burkholderia cenocepacia bacteria, more phage particles are produced in the presence of subinhibitory concentrations of meropenem, ciprofloxacin, and tetracycline [2]. Subinhibitory concentrations of tetracycline ensure clustering of bacterial cells and minimize their lateral movement, which helps phages find and infect a larger number of bacteria [2]. Interestingly, increased phage replication is also observed in cases where the bacteria are resistant to the antibiotic being used [2]. A combination of phages with subinhibitory concentrations of ciprofloxacin and meropenem suppressed the growth of phage-resistant mutants in animal endocarditis models and thus improved the results of phage therapy [3].

Combining phage preparations with antibiotics opens up new possibilities for overcoming bacterial resistance to both. For example, some phages infect Gram-negative bacteria by binding to the TolC protein on their surface, which is a component of the efflux pump—an enzyme that effluxes drugs from the cell and thus confers resistance to them. If TolC is mutant, the phage can no longer penetrate the bacterium, but this mutation restores the bacterium's sensitivity to antibiotics [4]. Similarly, the OMKO1 phage infects P. aeruginosa by interacting with the MexAB/MexXY efflux pump protein. Mutations in the pump proteins disrupt the phage's ability to infect the bacterium, but the bacterium becomes sensitive to ciprofloxacin [5].

Adjuvants are also used to enhance the effect of bacteriophages in biofilms, which are known to often be an obstacle to the treatment of bacterial infections. Although phages have the ability to destroy biofilms, it is advisable to enhance this property. DNA can be used as adjuvants for phages; it destroys extracellular bacterial DNA, which plays a key role in the aggregation of the latter and the interaction of biofilms with leukocytes during the development of the inflammatory response [6]. Alcohols such as xylitol, sorbitol, and erythritol can also act as adjuvants for phages—they penetrate biofilms, where they accumulate as toxic, non-metabolizable phosphates, thereby inhibiting bacterial growth [7].

A significant effect in killing bacteria in biofilms can be achieved by combining phages and antibiotics. Adding phages to antibiotics also allows for a reduction in the effective dose of antibiotics [8,9].

On the other hand, antagonistic relationships between phages and antibiotics are possible. Quinolones have been shown to have a synergistic effect on bacteriophages in one study, but an antagonistic effect in another [5,10]. High doses of antibiotics can also inhibit bacteriophage replication [8]. Such problems are particularly common with antibiotics that interfere with bacterial protein synthesis [11].

From a clinical perspective, the use of combinations of bacteriophages and antibiotics could extend the lifespan of currently available antimicrobial agents and facilitate the development of phage therapy. Unfortunately, in most cases, the mechanisms underlying the synergistic action of antibiotics and bacteriophages remain unknown. Therefore, further testing—both in animals and in clinical settings—is still needed.

Source : Luong T, Salabarria A-Ch, Roach DR. Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going? Clinical Therapeutics, 31 August 2020. https://doi.org/10.1016/j.clinthera.2020.07.014

Literature

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