Affiliation:
1. College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
2. Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, China
Abstract
ABSTRACT
Phage therapy has become a viable antimicrobial treatment as an alternative to antibiotic treatment, with an increase in antibiotic resistance. Phage resistance is a major limitation in the therapeutic application of phages, and the lack of understanding of the dynamic changes between bacteria and phages constrains our response strategies to phage resistance. In this study, we investigated the changing trends of mutual resistance between
Stenotrophomonas maltophilia
(
S. maltophilia
) and its lytic phage, BUCT603. Our results revealed that
S. maltophilia
resisted phage infection through mutations in the cell membrane proteins, while the evolved phage re-infected the resistant strain primarily through mutations in structure-related proteins. Compared with the wild-type strain (SMA118), the evolved phage-resistant strain (R118-2) showed reduced virulence, weakened biofilm formation ability, and reduced resistance to aminoglycosides. In addition, the evolved phage BUCT603B1 in combination with kanamycin could inhibit the development of phage-resistant
S. maltophilia in vitro
and significantly improve the survival rate of
S. maltophilia
-infected mice. Altogether, these results suggest that
in vitro
characterization of bacteria-phage co-evolutionary relationships is a useful research tool to optimize phages for the treatment of drug-resistant bacterial infections.
IMPORTANCE
Phage therapy is a promising approach to treat infections caused by drug-resistant
Stenotrophomonas maltophilia (S. maltophilia)
. However, the rapid development of phage resistance has hindered the therapeutic application of phages.
In vitro
evolutionary studies of bacteria–phage co-cultures can elucidate the mechanism of resistance development between phage and its host. In this study, we investigated the resistance trends between
S. maltophilia
and its phage and found that inhibition of phage adsorption is the primary strategy by which bacteria resist phage infection
in vitro
, while phages can re-infect bacterial cells by identifying other adsorption receptors. Although the final bacterial mutants were no longer infected by phages, they incurred a fitness cost that resulted in a significant reduction in virulence. In addition, the combination treatment with phage and aminoglycoside antibiotics could prevent the development of phage resistance in
S. maltophilia in vitro
. These findings contribute to increasing the understanding of the co-evolutionary relationships between phages and
S. maltophilia
.
Funder
The National Key Research and Development Program of China; Funds for First-Class Discipline Construction
Innovation and Transfer Fund of Peking University Third Hospital
Military Biosecurity Research Program
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology