A1 Journal article (refereed)
Adapting a Phage to Combat Phage Resistance (2020)

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

JYU authors or editors

Publication details

All authors or editors: Laanto, Elina; Mäkelä, Kati; Hoikkala, Ville; Ravantti, Janne J.; Sundberg, Lotta-Riina

Journal or series: Antibiotics

eISSN: 2079-6382

Publication year: 2020

Volume: 9

Issue number: 6

Article number: 291

Publisher: MDPI

Publication country: Switzerland

Publication language: English

DOI: https://doi.org/10.3390/antibiotics9060291

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/69724

Abstract

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.

Keywords: bacteriophages; phage therapy; fish diseases; drug resistance; evolution

Free keywords:  coevolution; fish pathogen; phage resistance; phage therapy

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Ministry reporting: Yes

Reporting Year: 2020

JUFO rating: 1