Phage-Derived Depolymerase as an Antibiotic Adjuvant Against Multidrug-Resistant Acinetobacter Baumannii

Abstract

Bacteriophage-encoded depolymerases are responsible for degrading capsular polysaccharides (CPS), lipopolysaccharides (LPS) and exopolysachcharides (EPS) of the host bacteria during phage invasion. They have been considered as promising antivirulence agents in controlling bacterial infections, including those caused by drug-resistant bacteria. This feature inspires a hope of utilizing these enzymes to disarm the polysaccharide capsid of the bacterial cells, which then strengthens the action of antibiotics. Here we have identified, cloned, and expressed a depolymerase Dpo71 from a bacteriophage specific for the gram-negative (G-ve) bacterium Acinetobacter baumannii in the heterologous host E. coli. Dpo71 sensitizes the multidrug-resistant (MDR) A. baumannii to the host immune attack, and also acts as an adjuvant to assist or boost the action of antibiotics, for example colistin. Specifically, Dpo71 at 10 µg/ml enables a complete bacterial eradication by human serum at 50% volume ratio. Dpo71 inhibits biofilm formation and disrupts the pre-formed biofilm. Combination of Dpo71 could significantly enhance the antibiofilm activity of colistin, and improve the survival rate of A. baumannii infected Galleria mellonella. Dpo71 retains the strain-specificity of the parent phage from which Dpo71 is derived: the phage-sensitive A. baumannii strains respond to Dpo71 treatment, whereas the phage-insensitive strains do not. This indicates that Dpo71 indeed is responsible for the host specificity of bacteriophages. In summary, our work demonstrates the feasibility of using recombinant depolymerases as an antibiotic adjuvants to supplement the development of new antibacterials and to battle against MDR pathogens.

Bacteriophage-Mediated Control of Biofilm: A Promising New Dawn for the Future

“…Recent studies have shed light on the potential of combining depolymerases with other compounds. Chen et al (2021) identified during a trial, a depolymerase Dpo71 from an A. baumannii phage in the heterologous host E. coli to combat multidrug-resistant A. baumannii . The team concluded after further research that Dpo71 presented the ability to enhance antibiotic activity, specifically colistin, and demonstrated that at 10 μg/ml, Dpo71 enabled a total eradication of human serum bacteria at 50% volume ratio.…”

“…Dpo71 was also able to inhibit both existing as well as new biofilm formation. Chen et al further proposed that the potential combination therapy of Dpo71 with colistin could enhance antibiofilm capabilities, therefore, increasing the survival rate of infected patients ( Chen et al, 2021 ). A further list of recent combination therapy is demonstrated in Table 4 .…”

Mitigation of evolved bacterial resistance to phage therapy

“…Combining antibiotics with phagederived enzymes such as lysins, holins or depolymerases, can also boost the antimicrobial effect and significantly constrain resistance [15]. A depolymerase specific to Acinetobacter baumannii in addition to antibiotics, decreased bacterial population sizes, treatment-resistance frequency and biofilm formation in vitro [16]. Resistance frequency in bacteria against these phagederived proteins had never previously been recorded [17].…”