Engineered phage with cell-penetrating peptides for intracellular bacterial infections
ABSTRACT Salmonella infection poses a critical challenge to global public health, and the situation is exacerbated by the increasing prevalence of antibiotic resistance. Bacteriophages (phages) are increasingly being used as antimicrobial agents due to their ability to kill specific bacteria. Howeve...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-10-01
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| Series: | mSystems |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/msystems.00646-23 |
| _version_ | 1797617671652507648 |
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| author | Min Zhao Xin Tan Zi-qiang Liu Lei Dou Dong Liu Yong-jun Pan Ying-fei Ma Jia-lin Yu |
| author_facet | Min Zhao Xin Tan Zi-qiang Liu Lei Dou Dong Liu Yong-jun Pan Ying-fei Ma Jia-lin Yu |
| author_sort | Min Zhao |
| collection | DOAJ |
| description | ABSTRACT Salmonella infection poses a critical challenge to global public health, and the situation is exacerbated by the increasing prevalence of antibiotic resistance. Bacteriophages (phages) are increasingly being used as antimicrobial agents due to their ability to kill specific bacteria. However, the low cellular uptake of phages has limited their use in treating intracellular bacterial infections. Here, we present a study using engineered phages with cell-penetrating peptides (CPPs) for enhancing the internalization efficiency of phages to inhibit bacterial intracellular infections. Through bioinformatic analysis, we identified a phage-encoded protein harboring an immunoglobulin-like (Ig-like) domain as the potential target for phage display. Using a CRISPR-Cas9-based method, we successfully displayed short peptides on GP94, an Ig-like domain-containing protein, of Salmonella phage selz. We improved phage intracellular uptake in multiple cell types by fusion of various CPPs to GP94. Notably, the phage selzHA-TAT showed promising results in enhancing the intracellular inhibition of Salmonella in different cells. Our research provides a straightforward strategy for displaying CPPs on non-model phages, offering a promising novel and effective therapeutic approach for treating intracellular and drug-resistant bacteria. IMPORTANCE Salmonella infection is a significant threat to global public health, and the increasing prevalence of antibiotic resistance exacerbates the situation. Therefore, finding new and effective ways to combat this pathogen is essential. Phages are natural predators of bacteria and can be used as an alternative to antibiotics to kill specific bacteria, including drug-resistant strains. One significant limitation of using phages as antimicrobial agents is their low cellular uptake, which limits their effectiveness against intracellular bacterial infections. Therefore, finding ways to enhance phage uptake is crucial. Our study provides a straightforward strategy for displaying cell-penetrating peptides on non-model phages, offering a promising novel and effective therapeutic approach for treating intracellular and drug-resistant bacteria. This approach has the potential to address the global challenge of antibiotic resistance and improve public health outcomes. |
| first_indexed | 2024-03-11T07:59:06Z |
| format | Article |
| id | doaj.art-c1667747fad84243a7d2666e8ab9af8e |
| institution | Directory Open Access Journal |
| issn | 2379-5077 |
| language | English |
| last_indexed | 2024-03-11T07:59:06Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSystems |
| spelling | doaj.art-c1667747fad84243a7d2666e8ab9af8e2023-11-17T03:22:37ZengAmerican Society for MicrobiologymSystems2379-50772023-10-018510.1128/msystems.00646-23Engineered phage with cell-penetrating peptides for intracellular bacterial infectionsMin Zhao0Xin Tan1Zi-qiang Liu2Lei Dou3Dong Liu4Yong-jun Pan5Ying-fei Ma6Jia-lin Yu7Department of Neonatology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Key Laboratory of Pediatrics , Chongqing, ChinaCAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences , Shenzhen, ChinaCAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences , Shenzhen, ChinaDepartment of Neonatology, Southern University of Science and Technology Hospital , Shenzhen, ChinaDepartment of Neonatology, Shenzhen People’s Hospital , Shenzhen, ChinaDepartment of Critical Care Medicine, Southern University of Science and Technology Hospital , Shenzhen, ChinaCAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences , Shenzhen, ChinaDepartment of Neonatology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Key Laboratory of Pediatrics , Chongqing, ChinaABSTRACT Salmonella infection poses a critical challenge to global public health, and the situation is exacerbated by the increasing prevalence of antibiotic resistance. Bacteriophages (phages) are increasingly being used as antimicrobial agents due to their ability to kill specific bacteria. However, the low cellular uptake of phages has limited their use in treating intracellular bacterial infections. Here, we present a study using engineered phages with cell-penetrating peptides (CPPs) for enhancing the internalization efficiency of phages to inhibit bacterial intracellular infections. Through bioinformatic analysis, we identified a phage-encoded protein harboring an immunoglobulin-like (Ig-like) domain as the potential target for phage display. Using a CRISPR-Cas9-based method, we successfully displayed short peptides on GP94, an Ig-like domain-containing protein, of Salmonella phage selz. We improved phage intracellular uptake in multiple cell types by fusion of various CPPs to GP94. Notably, the phage selzHA-TAT showed promising results in enhancing the intracellular inhibition of Salmonella in different cells. Our research provides a straightforward strategy for displaying CPPs on non-model phages, offering a promising novel and effective therapeutic approach for treating intracellular and drug-resistant bacteria. IMPORTANCE Salmonella infection is a significant threat to global public health, and the increasing prevalence of antibiotic resistance exacerbates the situation. Therefore, finding new and effective ways to combat this pathogen is essential. Phages are natural predators of bacteria and can be used as an alternative to antibiotics to kill specific bacteria, including drug-resistant strains. One significant limitation of using phages as antimicrobial agents is their low cellular uptake, which limits their effectiveness against intracellular bacterial infections. Therefore, finding ways to enhance phage uptake is crucial. Our study provides a straightforward strategy for displaying cell-penetrating peptides on non-model phages, offering a promising novel and effective therapeutic approach for treating intracellular and drug-resistant bacteria. This approach has the potential to address the global challenge of antibiotic resistance and improve public health outcomes.https://journals.asm.org/doi/10.1128/msystems.00646-23phage engineeringcell-penetrating peptidephage therapyintracellular infection |
| spellingShingle | Min Zhao Xin Tan Zi-qiang Liu Lei Dou Dong Liu Yong-jun Pan Ying-fei Ma Jia-lin Yu Engineered phage with cell-penetrating peptides for intracellular bacterial infections mSystems phage engineering cell-penetrating peptide phage therapy intracellular infection |
| title | Engineered phage with cell-penetrating peptides for intracellular bacterial infections |
| title_full | Engineered phage with cell-penetrating peptides for intracellular bacterial infections |
| title_fullStr | Engineered phage with cell-penetrating peptides for intracellular bacterial infections |
| title_full_unstemmed | Engineered phage with cell-penetrating peptides for intracellular bacterial infections |
| title_short | Engineered phage with cell-penetrating peptides for intracellular bacterial infections |
| title_sort | engineered phage with cell penetrating peptides for intracellular bacterial infections |
| topic | phage engineering cell-penetrating peptide phage therapy intracellular infection |
| url | https://journals.asm.org/doi/10.1128/msystems.00646-23 |
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