Evolutionary Dynamics between Phages and Bacteria as a Possible Approach for Designing Effective Phage Therapies against Antibiotic-Resistant Bacteria

Abstract

With the increasing global threat of antibiotic resistance, there is an urgent need to develop new effective therapies to tackle antibiotic-resistant bacterial infections. Bacteriophage therapy is considered as a possible alternative over antibiotics to treat antibiotic-resistant bacteria. However, bacteria can evolve resistance towards bacteriophages through antiphage defense mechanisms, which is a major limitation of phage therapy. The antiphage mechanisms target the phage life cycle, including adsorption, the injection of DNA, synthesis, the assembly of phage particles, and the release of progeny virions. The non-specific bacterial defense mechanisms include adsorption inhibition, superinfection exclusion, restriction-modification, and abortive infection systems. The antiphage defense mechanism includes a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system. At the same time, phages can execute a counterstrategy against antiphage defense mechanisms. However, the antibiotic susceptibility and antibiotic resistance in bacteriophage-resistant bacteria still remain unclear in terms of evolutionary trade-offs and trade-ups between phages and bacteria. Since phage resistance has been a major barrier in phage therapy, the trade-offs can be a possible approach to design effective bacteriophage-mediated intervention strategies. Specifically, the trade-offs between phage resistance and antibiotic resistance can be used as therapeutic models for promoting antibiotic susceptibility and reducing virulence traits, known as bacteriophage steering or evolutionary medicine. Therefore, this review highlights the synergistic application of bacteriophages and antibiotics in association with the pleiotropic trade-offs of bacteriophage resistance.

Keywords: CRISPR–Cas; abortive infection; phage resistance; restriction modification; superinfection exclusion; trade-off.

Figure 1

Overview of bacterial antiphage defense mechanisms. 1. Phage infection: successful phage attachment and infection; 2. competition in receptor binding: blocking of the phage-binding receptor to evade phage attachment; 3. alteration in cell surface receptor: mutation or phase variation in the receptor to avoid phage attachment; 4. hiding phage receptor: production of extracellular polysaccharides to hide phage receptor; 5. superinfection exclusion—A: integration of prophage into host genome; B: expression of protein to block DNA entry; C: exclusion of superinfection; 6. restriction-modification system—A: recognition of restriction site; B: cleaving of inserted phage DNA; 7. CRISPR–Cas immunity; 8. toxin–antitoxin immunity—A: antitoxin neutralizes toxin before phage infection; B: phage infection-mediated liberation of toxin to induce reduced metabolism or cell death; 9. abortive infection—A: phage infection mediates expression of abortive infection mechanism; B: release of unassembled phage particles from the host cell.