A combination therapy of Phages and Antibiotics: Two is better than one

Abstract

Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.

Keywords: bacterial anti-phage resistance; biofilm; multidrug-resistance; phage therapy; phage-antibiotic synergy.

Figure 1

Trade-off in bacteria between phage resistance and bacterial fitness; Profile of proteins found on the surface of bacteria including nutrient channels, lipopolysaccharide (LPS), drug efflux pumps, and siderophore receptors. They are related to bacterial life history traits and initial infection of phage. When the genes encoding these proteins are altered, through events such as mutations, the bacteria exhibit the characteristics of phage resistance. In addition, these changes separately block bacterial intake of nutrients, downregulate virulence factors, and hinder entry of iron ion into bacteria, thus affecting normal growth of bacteria. Moreover, the blocked drug efflux system predisposes bacteria to antibiotics.