Adapting a Phage to Combat Phage Resistance
Laanto, E., Mäkelä, K., Hoikkala, V., Ravantti, J. J., & Sundberg, L.-R. (2020). Adapting a Phage to Combat Phage Resistance. Antibiotics, 9(6), Article 291. https://doi.org/10.3390/antibiotics9060291
DisciplineSolu- ja molekyylibiologiaBiologisten vuorovaikutusten huippututkimusyksikköNanoscience CenterCell and Molecular BiologyCentre of Excellence in Biological Interactions ResearchNanoscience Center
© 2020 by the authors. Licensee MDPI, Basel, Switzerland
Phage therapy is becoming a widely recognized alternative for fighting pathogenic bacteria due to increasing antibiotic resistance problems. However, one of the common concerns related to the use of phages is the evolution of bacterial resistance against the phages, putatively disabling the treatment. Experimental adaptation of the phage (phage training) to infect a resistant host has been used to combat this problem. Yet, there is very little information on the trade-offs of phage infectivity and host range. Here we co-cultured a myophage FCV-1 with its host, the fish pathogen Flavobacterium columnare, in lake water and monitored the interaction for a one-month period. Phage resistance was detected within one day of co-culture in the majority of the bacterial isolates (16 out of the 18 co-evolved clones). The primary phage resistance mechanism suggests defense via surface modifications, as the phage numbers rose in the first two days of the experiment and remained stable thereafter. However, one bacterial isolate had acquired a spacer in its CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)-Cas locus, indicating that also CRISPR-Cas defense was employed in the phage-host interactions. After a week of co-culture, a phage isolate was obtained that was able to infect 18 out of the 32 otherwise resistant clones isolated during the experiment. Phage genome sequencing revealed several mutations in two open reading frames (ORFs) likely to be involved in the regained infectivity of the evolved phage. Their location in the genome suggests that they encode tail genes. Characterization of this evolved phage, however, showed a direct cost for the ability to infect several otherwise resistant clones—adsorption was significantly lower than in the ancestral phage. This work describes a method for adapting the phage to overcome phage resistance in a fish pathogenic system. ...
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Related funder(s)Academy of Finland
Funding program(s)Academy Project, AoF
Additional information about fundinghis research was funded by the Academy of Finland grants #321985 (EL) and #314939 (LRS) and Jane and Aatos Erkko Foundation. This work resulted from the BONUS Flavophage project supported by BONUS (Art 185), funded jointly by the European Union (EU) and the Academy of Finland.
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