Fitness Trade-Offs Resulting from Bacteriophage Resistance Potentiate Synergistic Antibacterial Strategies

Abstract

Bacteria that cause life-threatening infections in humans are becoming increasingly difficult to treat. In some instances, this is due to intrinsic and acquired antibiotic resistance, indicating that new therapeutic approaches are needed to combat bacterial pathogens. There is renewed interest in utilizing viruses of bacteria known as bacteriophages (phages) as potential antibacterial therapeutics. However, critics suggest that similar to antibiotics, the development of phage-resistant bacteria will halt clinical phage therapy. Although the emergence of phage-resistant bacteria is likely inevitable, there is a growing body of literature showing that phage selective pressure promotes mutations in bacteria that allow them to subvert phage infection, but with a cost to their fitness. Such fitness trade-offs include reduced virulence, resensitization to antibiotics, and colonization defects. Resistance to phage nucleic acid entry, primarily via cell surface modifications, compromises bacterial fitness during antibiotic and host immune system pressure. In this minireview, we explore the mechanisms behind phage resistance in bacterial pathogens and the physiological consequences of acquiring phage resistance phenotypes. With this knowledge, it may be possible to use phages to alter bacterial populations, making them more tractable to current therapeutic strategies.

High-throughput mapping of the phage resistance landscape in E. coli

“…In particular, identification of phages that differ in their receptor use or against which cross-resistance is unlikely to evolve would allow for better design of such therapies [ 23 , 37 , 242 ]. Moreover, identifying phages that select for resistance that have interrelated phenotypic consequences with, for example, antibiotic sensitivity is a recent advancement in the field that could directly benefit from these screening approaches [ 33 , 53 , 97 , 243 ]. By combining fitness datasets for phages and antibiotics or phage-antibiotic combination therapies [ 244 – 246 ], such screens could provide an avenue for performing high-throughput search for genetic trade-offs or “evolutionary traps” [ 33 , 53 , 97 , 243 ] that could provide a much-needed solution to overcome the antibiotic-resistance pandemic.…”

Considerations for Phage Therapy Against Mycobacterium abscessus

“…Modifications in polysaccharides, teichoic acids, and outer membrane proteins block phage adsorption in Gram-positive bacteria. However, phage-resistant variants are often balanced with bacteria-fitness costs usually associated with decreased virulence or higher susceptibility to antibiotics ( Mangalea and Duerkop, 2020 ), although a faster growth-rate derivative has also been described ( Kashiwagi and Yomo, 2011 ). Temperate phages may represent an obstacle for the entry of invasive phages, the analysis of temperate mycobacteriophages infecting M. tuberculosis and M. smegmatis exhibited at least five types of defense systems that avoided phage infection ( Dedrick et al, 2017 ), although phages can in turn escape these mechanisms ( Hatfull, 2020 ).…”

Lytic bacteriophages facilitate antibiotic sensitization ofEnterococcus faecium

“…With renewed interest focused on utilizing lytic phages for the treatment of bacterial infections and the observation that phage resistance can be a fitness tradeoff under antibiotic pressure (26, 27), we sought to determine the impact of E. faecium phage resistance on antimicrobial susceptibility. We performed antimicrobial susceptibility screening using E-test strips for the phage 9181, 9183, and 9184 resistant mutants compared to their parental strains to determine if phage resistance altered E. faecium antimicrobial susceptibility.…”