Use of bacteriophage to target bacterial surface structures required for virulence: a systematic search for antibiotic alternatives

Abstract

Bacteriophage (phage) that infect pathogenic bacteria often attach to surface receptors that are coincidentally required for virulence. Receptor loss or modification through mutation renders mutants both attenuated and phage resistant. Such attenuated mutants frequently have no apparent laboratory growth defects, but in the host, they fail to exhibit properties needed to produce disease such as mucosal colonization or survival within professional phagocytic cells. The connection between attenuation and phage resistance has been exploited in experimental demonstrations of phage therapy. In such experiments, phage resistant mutants that arise naturally during therapy are inconsequential because of their attenuated status. A more contemporary approach to exploiting this connection involves identifying small effector molecules, identified in high throughput screens, that inhibit one or more of the steps needed to produce a functioning phage receptor. Since such biosynthetic steps are unique to bacteria, inhibitors can be utilized therapeutically, in lieu of antibiotics. Also, since the inhibitor is specific to a particular bacterium or group of bacteria, no off-target resistance is generated in the host’s commensal bacterial population. This brief review covers examples of how mutations that confer phage resistance produce attenuation, and how this coincidental relationship can be exploited in the search for the next generation of therapeutic agents for bacterial diseases.

Characterization and genome annotation of a newly detected bacteriophage infecting multidrug-resistant Acinetobacter baumannii

“…The high mutation rate of bacteriophages makes it difficult to identify gene functions [ 18 ], and this lack of information limits their application and causes uncertainty regarding their safety [ 19 , 20 ]. There are many similarities between the genes of φAbp2 and those of previously identified bacteriophages.…”

The role of the microbiome in human health and disease: an introduction for clinicians

“…123 Although bacteriophages are known to select for bacterial variants that are resistant, these resistant bacteria often have altered surface structures that while leading to phage resistance also attenuate virulence within the host. 124 Much more work is needed before bacteriophages can be developed into therapeutic agents, 125 but there is much interest in exploring novel therapies designed to minimize microbiome disruption.…”

Bacteriophage-mediated identification of bacteria using photoacoustic flow cytometry

“…45 Conversely, bacteriophages have evolved to use surface epitopes that are essential and difficult to change. 46 Bacteriophages have even been shown to target cell surface pumps used in bacterial antibiotic resistance. Though bacteriophage resistance can evolve, it happens at a much lower rate than antibody avoidance and always has a negative fitness effect on the bacteria.…”