Bacteriophages at the Chemistry Interface: Chemical, Genomic, and Structural Strategies for Targeted Therapeutics

This review examines the molecular chemistry and structural biology of bacteriophages as emerging targeted therapeutics, focusing on how chemical and genetic engineering can enhance phage specificity and therapeutic potential to address antimicrobial resistance. A narrative review was conducted following the Assessment of Narrative Review Articles (SANRA) guidelines. Literature searches in PubMed, Scopus, and Google Scholar (۲۰۱۵–۲۰۲۶, with inclusion of earlier seminal studies where necessary) used terms including "bacteriophage", "phage therapy", "endolysin", "holin", "phage engineering", "chemical modification", and "genomics". Studies were included if they were relevant to phage structural biology, enzymatic lysis, chemical modification, genomic annotation, or therapeutic development. Non-English publications and standalone conference abstracts were excluded. Forty references met inclusion criteria. Bacteriophages show species- and strain-specific host recognition mediated by tail fiber and baseplate variation; furthermore, genome-packaging efficiency differs among phage types, influencing replication and burst size. Chemical modifications, including conjugation of polyethylene glycol (PEG) chains (PEGylation) and surface ligand conjugation, improve phage stability, circulation time, and bacterial targeting, while clustered regularly interspaced short palindromic repeats (CRISPR)-based engineering enables customized host specificity. Hybrid phage–nanoparticle systems further enhance delivery precision and biofilm penetration. Collectively, these findings show that rational design and molecular engineering can transform natural phages into programmable therapeutic agents. Bacteriophages can be chemically and genetically engineered to enhance specificity and therapeutic potential. Their structure–function relationships, enzymatic precision, and genomic adaptability position them as promising agents against multidrug-resistant pathogens. Integrating chemistry, bioinformatics, and synthetic biology supports next-generation phage therapeutics with improved targeting and efficacy; however, programmability currently relies on empirically guided engineering rather than fully predictable design frameworks, underscoring the need for continued mechanistic research.This review examines the molecular chemistry and structural biology of bacteriophages as emerging targeted therapeutics, focusing on how chemical and genetic engineering can enhance phage specificity and therapeutic potential to address antimicrobial resistance. A narrative review was conducted following the Assessment of Narrative Review Articles (SANRA) guidelines. Literature searches in PubMed, Scopus, and Google Scholar (۲۰۱۵–۲۰۲۶, with inclusion of earlier seminal studies where necessary) used terms including "bacteriophage", "phage therapy", "endolysin", "holin", "phage engineering", "chemical modification", and "genomics". Studies were included if they were relevant to phage structural biology, enzymatic lysis, chemical modification, genomic annotation, or therapeutic development. Non-English publications and standalone conference abstracts were excluded. Forty references met inclusion criteria. Bacteriophages show species- and strain-specific host recognition mediated by tail fiber and baseplate variation; furthermore, genome-packaging efficiency differs among phage types, influencing replication and burst size. Chemical modifications, including conjugation of polyethylene glycol (PEG) chains (PEGylation) and surface ligand conjugation, improve phage stability, circulation time, and bacterial targeting, while clustered regularly interspaced short palindromic repeats (CRISPR)-based engineering enables customized host specificity. Hybrid phage–nanoparticle systems further enhance delivery precision and biofilm penetration. Collectively, these findings show that rational design and molecular engineering can transform natural phages into programmable therapeutic agents. Bacteriophages can be chemically and genetically engineered to enhance specificity and therapeutic potential. Their structure–function relationships, enzymatic precision, and genomic adaptability position them as promising agents against multidrug-resistant pathogens. Integrating chemistry, bioinformatics, and synthetic biology supports next-generation phage therapeutics with improved targeting and efficacy; however, programmability currently relies on empirically guided engineering rather than fully predictable design frameworks, underscoring the need for continued mechanistic research.

کلیدواژه ها:

Bacteriophages ، Phage therapy ، Synthetic biology ، Endolysins ، Holins ، Nanomedicine ، Genomics ، Antimicrobial resistance