Genetic and Phenotypic Analysis of Phage-Resistant Mutant Fitness Triggered by Phage–Host Interactions

Author:

Mi Yanze1,He Yile1,Mi Jinhui1,Huang Yunfei1,Fan Huahao1ORCID,Song Lihua1,An Xiaoping1,Xu Shan1,Li Mengzhe1,Tong Yigang12ORCID

Affiliation:

1. College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China

2. Beijing Advanced Innovation Center for Soft Matter Science and Engineering (BAIC-SM), Beijing University of Chemical Technology, Beijing 100029, China

Abstract

The emergence of phage-resistant bacterial strains is one of the biggest challenges for phage therapy. However, the emerging phage-resistant bacteria are often accompanied by adaptive trade-offs, which supports a therapeutic strategy called “phage steering”. The key to phage steering is to guide the bacterial population toward an evolutionary direction that is favorable for treatment. Thus, it is important to systematically investigate the impacts of phages targeting different bacterial receptors on the fitness of the bacterial population. Herein, we employed 20 different phages to impose strong evolutionary pressure on the host Pseudomonas aeruginosa PAO1 and examined the genetic and phenotypic responses of their phage-resistant mutants. Among these strains with impaired adsorptions, four types of mutations associated with bacterial receptors were identified, namely, lipopolysaccharides (LPSs), type IV pili (T4Ps), outer membrane proteins (OMPs), and exopolysaccharides (EPSs). PAO1, responding to LPS- and EPS-dependent phage infections, mostly showed significant growth impairment and virulence attenuation. Most mutants with T4P-related mutations exhibited a significant decrease in motility and biofilm formation ability, while the mutants with OMP-related mutations required the lowest fitness cost out of the bacterial populations. Apart from fitness costs, PAO1 strains might lose their resistance to antibiotics when counteracting with phages, such as the presence of large-fragment mutants in this study, which may inspire the usage of phage–antibiotic combination strategies. This work provides methods that leverage the merits of phage resistance relative to obtaining therapeutically beneficial outcomes with respect to phage-steering strategies.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Key Research and Development Program of Hebei Province

China Postdoctoral Science Foundation

Innovation & Transfer Fund of Peking University Third Hospital

Military Biosecurity Research Program

Key Project of Beijing University of Chemical Technology

Funds for First-class Discipline Construction

Fundamental Research Funds for Central Universities

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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