Genome-driven elucidation of phage-host interplay and impact of phage resistance evolution on bacterial fitness

Abstract

When considering the interactions between bacteriophages and their host, the issue of phage-resistance emergence is a key element in understanding the ecological impact of phages on the bacterial population. It is also an essential parameter for the implementation of phage therapy to combat antibiotic-resistant pathogens. This study investigates the phenotypic and genetic responses of five Pseudomonas aeruginosa strains (PAO1, A5803, AA43, CHA, and PAK) to the infection by seven phages with distinct evolutionary backgrounds and recognised receptors (LPS/T4P). Emerging phage-insensitivity was generally accompanied by self and cross-resistance mechanisms. Significant differences were observed between the reference PAO1 responses compared to other clinical representatives. LPS-dependent phage infections in clinical strains selected for mutations in the “global regulatory” and “other” genes, rather than in the LPS-synthesis clusters detected in PAO1 clones. Reduced fitness, as proxied by the growth rate, was correlated with large deletion (20–500 kbp) and phage carrier state. Multi-phage resistance was significantly correlated with a reduced growth rate but only in the PAO1 population. In addition, we observed that the presence of prophages decreased the lytic phage maintenance seemingly protecting the host against carrier state and occasional lytic phage propagation, thus preventing a significant reduction in bacterial growth rate.

Phenotypic and Genomic Comparison of Klebsiella pneumoniae Lytic Phages: vB_KpnM-VAC66 and vB_KpnM-VAC13

“…Large phages may have arisen from short phages that acquired novel genetic functions, which probably conferred them some evolutionary advantages. It has also been described that large phages appeared to be much more efficient in the long-term maintenance in the bacterial population than short phages [45]. Even if their use in phage therapy needs to be further studied and validated, vB_KpnM-VAC13 has already shown good antibacterial activity both in vitro and in an in vivo model combined with imipenem and the repurposed drug mitomycin C [12].…”

Targeted IS-element sequencing uncovers transposition dynamics during selective pressure in enterococci

“…Phage therapy case studies show that these viruses can be efficacious against refractory MDR bacteria in human patients 13, 14, 15, 16, 17 . However, bacterial resistance to phage infection develops quickly 18, 19, 20, 21 and the lessons learned from the past century of antibiotic use suggest that bacteria will gain resistance to phage infection after widespread phage treatment 22 . Acquired phage resistance, although beneficial to bacteria in the face of phage pressure, can come with fitness costs that dampen antibiotic resistance and virulence 12, 23, 24, 25 .…”

Mitigation of evolved bacterial resistance to phage therapy

“…Phage cocktails are of long-standing interest in phage therapy and offer a major strategy to reduce resistance evolution in bacteria. Multiple phages that target different receptors in bacteria should diversify which counter-defenses must be used by bacteria, likely diminishing or preventing the evolution of phage-resistance [9,10]. For instance, a combination of 5 phages based on maximising host range of Mycobacterium tuberculosis strains resulted in reduced persistence and reduced phage-resistance evolution, thus enhancing survival of the Galleria mellonella insect model [11].…”