Phage and CRISPR based precision antimicrobials: a dual strategy against multidrug-resistant bacteria

The rapid global emergence of multidrug-resistant (MDR) bacterial pathogens has significantly reduced the effectiveness of conventional antibiotics, creating an urgent need for alternative antimicrobial strategies. Among emerging precision therapeutics bacteriophage therapy and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas systems have shown to have strong potential through highly specific bacterial targeting mechanisms. Bacteriophages have the ability to replicate themselves and penetrate biofilms, and the ability of CRISPR-Cas systems to edit the genes responsible for antimicrobial resistance, virulence factors, and the mobile genetic elements that underlie bacterial resistance. The recent advancement enabled the integration of these technologies through CRISPR-armed bacteriophages, which utilize bacteriophages as delivery mechanisms for CRISPR and address the large populations of MDR bacteria. Compared to administering CRISPR and bacteriophage independently, the current data suggest that the use of these two methods synergistically will lead to greater efficacy of delivery, specific targeting of resistance determinants, decreased risk of resistance development, and minimal impact on the body's beneficial microorganisms. While the potential combination of these approaches holds great promise to help combat the issue of MDR bacteria, there are still numerous barriers to overcome in order to implement these methods which include narrow phage host range, bacterial escape mechanisms, off-target CRISPR activity, anti-CRISPR proteins, host immune responses, and unresolved manufacturing and regulatory limitations. This review critically examines bacteriophage-based antimicrobials, CRISPR-Cas therapeutic systems, and their emerging integration as CRISPR-armed phages, highlighting their comparative advantages, current limitations, and future potential as promising targeted antimicrobial approach platforms requiring further clinical validation.