Abstract
Capsule depolymerase enzymes offer a promising class of new antibiotics. In vivo studies are encouraging but it is unclear how well this type of phage product will generalize in therapeutics, or whether different depolymerases against the same capsule function similarly. Here, in vivo efficacy was tested using cloned bacteriophage depolymerases against Escherichia coli strains with three different capsule types: K1, K5, and K30. When treating infections with the cognate capsule type in a mouse thigh model, the previously studied K1E depolymerase rescued poorly, whereas K1F, K1H, K5, and K30 depolymerases rescued well. K30 gp41 was identified as the catalytically active protein. In contrast to the in vivo studies, K1E enzyme actively degraded K1 capsule polysaccharide in vitro and sensitized K1 bacteria to serum killing. The only in vitro correlate of poor K1E performance in vivo was that the purified enzyme did not form the expected trimer. K1E appeared as an 18-mer which might limit its in vivo distribution. Overall, depolymerases were easily identified, cloned from phage genomes, and as purified proteins they proved generally effective.
Highlights
Both intact phages and their proteins are promising therapies for antibiotic resistant bacteria (Lewis, 2013; Drulis-Kawa et al, 2015; Abedon et al, 2017) especially given the current slow pace of new antibiotic discovery (Silver, 2011)
It has been realized that therapy may utilize phage proteins instead of intact phages
E. coli ATCC 23506 and E69 were used for propagation, respectively, of the coliphages K1-5 (Scholl et al, 2001, 2004) and K30 (Whitfield and Lam, 1986)
Summary
Both intact phages and their proteins are promising therapies for antibiotic resistant bacteria (Lewis, 2013; Drulis-Kawa et al, 2015; Abedon et al, 2017) especially given the current slow pace of new antibiotic discovery (Silver, 2011). Phage therapy’s advantages include high host specificity, amplification where bacteria are dense, an abundance and diversity of wild phages, and evolution in response to bacterial resistance (Weber-Dabrowska et al, 2016). It has been realized that therapy may utilize phage proteins instead of intact phages. These alternative technologies have many advantages of phages – an abundant and diverse collection of phage proteins occur in nature, evolved to act against bacteria, and they potentially overcome. Possible functions of capsules include protecting bacteria from desiccation, bacterial adherence to surfaces and to each other, helping bacteria escape complement-mediated killing or phagocytosis, and resisting immune response (Roberts, 1996). Further evidence of depolymerase efficacy is offered here for five different phage depolymerases against three capsule types in a mouse infection model
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