Phage-encoded depolymerases as a strategy for combating multidrug-resistant Acinetobacter baumannii

Abstract

Acinetobacter baumannii, a predominant nosocomial pathogen, represents a grave threat to public health due to its multiple antimicrobial resistance. Managing patients afflicted with severe infections caused by multiple drug-resistant A. baumannii is particularly challenging, given the associated high mortality rates and unfavorable prognoses. The diminishing efficacy of antibiotics against this superbug underscores the urgent necessity for novel treatments or strategies to address this formidable issue. Bacteriophage-derived polysaccharide depolymerase enzymes present a potential approach to combating this pathogen. These enzymes target and degrade the bacterial cell's exopolysaccharide, capsular polysaccharide, and lipopolysaccharide, thereby disrupting biofilm formation and impairing the bacteria's defense mechanisms. Nonetheless, the narrow host range of phage depolymerases limits their therapeutic efficacy. Despite the benefits of these enzymes, phage-resistant strains have been identified, highlighting the complexity of phage-host interactions and the need for further investigation. While preliminary findings are encouraging, current investigations are limited, and clinical trials are imperative to advance this treatment approach for broader clinical applications. This review explores the potential of phage-derived depolymerase enzymes against A. baumannii infections.

Keywords: bacteriophage; biofilm; depolymerase; drug resistance; polysaccharide.

Figure 1

Structure and mechanisms of action of bacteriophage depolymerases: (A) Distribution of depolymerase within the structure of bacteriophages (B) The overarching mechanisms by which depolymerases catalyze polysaccharide degradation involve two fundamental processes: hydrolysis and lysis. During hydrolysis, depolymerases enzymatically cleave the glycosidic bonds between sugar monomers, resulting in the fragmentation of polysaccharides into smaller sugar units. In the lysis process, these enzymes compromise the structural integrity of the polysaccharide matrix. Created with BioRender.com.

Figure 2

Illustration is the trimeric crystal structure of the tail spike protein. (A) gp49 tail spike protein (PDB ID: 6C72) derived from A. baumannii bacteriophage Fri1, a capsular polysaccharide depolymerase (Hydrolase). (B) Gp54 tail spike (PDB ID: 4Y9V) of A baumannii bacteriophage AP22 polysaccharide degrading lyase. Three monomers are marked by different colors. Created with BioRender.com.

Figure 3

The illustration delineates the anti-biofilm mechanisms of phage-encoded depolymerases: (A) Phage-encoded depolymerases impede biofilm formation by degrading the extracellular polysaccharides that protect the bacterial cells within the biofilm. (B) The synergistic application of phage-encoded depolymerases and antibiotics enhances the bactericidal efficacy against A. baumannii biofilms. The depolymerases degrade the extracellular polysaccharide, rendering the bacteria more susceptible to antibiotic treatment. (C) A consortium of phage-encoded depolymerases can effectively dismantle biofilms by degrading the polysaccharide matrix. (D) Phage-encoded depolymerases sensitize bacteria to the host immune response by degrading the protective polysaccharide matrix of biofilms. Created with BioRender.com.