Antibiotics stimulate protein transfer to persister cells.
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| Title: | Antibiotics stimulate protein transfer to persister cells. |
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| Authors: | Wen, Alice X. (AUTHOR), Bos, Julia (AUTHOR), Panda, Debojyoti (AUTHOR), Hagstrom, Katelin M. (AUTHOR), Singh, Shubham (AUTHOR), Mageswaran, Shrawan Kumar (AUTHOR), Wang, Xiaoli (AUTHOR), Hu, Bo (AUTHOR), Welch, Kobie T. (AUTHOR), Cooke, Matthew B. (AUTHOR), Halliday, Jennifer A. (AUTHOR), Deus Ramirez, Laura (AUTHOR), Martinez, Antoinette E. (AUTHOR), Chang, Yi-Wei (AUTHOR), Weitz, David A. (AUTHOR), Herman, Christophe (AUTHOR) |
| Source: | Science. 6/25/2026, Vol. 392 Issue 6805, p1-14. 14p. |
| Subjects: | Extracellular vesicles, Protein transport, Multidrug tolerance (Microbiology), Antibiotics, Escherichia coli |
| Abstract: | The exchange of biological matter between bacterial cells drives adaptation and evolution. However, whether bacteria can exchange functional proteins remains unclear. In this work, we found that antibiotic treatment can induce vesicle-mediated horizontal protein transfer within and between bacterial species. We developed a genetic system in Escherichia coli to track transfer events and performed single-cell transcriptomic profiling on an isogenic population of bacteria. Antibiotics stimulated the differentiation of this isogenic population into distinct cell states: donor cells that activated a membrane stress response to release protein-containing vesicles and recipient cells that suppressed this response to acquire protein from their neighbors. Protein uptake enhanced the antibiotic persistence of recipient cells, revealing that vesicle exchange promotes bacterial survival during antibiotic treatment. Editor's summary: In addition to killing bacteria, antibiotics can also promote adaptations that help bacteria survive. Wen et al. found that antibiotic stress triggers protein exchange between neighboring bacteria through membrane-bound vesicles (see the Perspective by Oms and Van Melderen). Some bacteria, especially dormant "persister" cells that normally turn off their protein synthesis, are more likely to take up these vesicles and use their contents to withstand antibiotic treatment. This process creates two transient cell states within an otherwise identical population: donor cells that release proteins and dormant recipient cells that receive them. By revealing how bacteria share proteins under antibiotic stress, this work uncovers a mechanism by which microbes can survive antibiotics and suggests potential strategies to target persistent infections. —Stella M. Hurtley INTRODUCTION: Bacterial cells exchange biological material, such as DNA and signaling molecules, to promote adaptation in stressful conditions, such as antibiotic exposure. Whereas horizontal gene transfer is known to spread antibiotic resistance genes, far less is understood about the mechanisms and effect of horizontal protein transfer. Bacterial membrane vesicles, which contain proteins, have been proposed as mediators of horizontal protein transfer. Additionally, antibiotic treatment stimulates vesicle production, suggesting a potential role for membrane vesicles in antibiotic survival. However, evidence for vesicle-mediated protein transfer remains indirect and correlative, which makes it difficult to rule out alternative mechanisms. To directly assess whether and how membrane vesicles contribute to protein transfer, a sensitive and specific method to detect transfer events is required. RATIONALE: To directly measure horizontal transfer, we constructed a genetic system in Escherichia coli consisting of a donor and a recipient strain. Donors express Cre recombinase, which activates a defective genetic marker in recipient cells, allowing individual transfer events to be detected. Using this approach, we tested whether antibiotics induce the transfer of Cre protein between cells and characterized the genetic and biochemical properties of the particles responsible. RESULTS: Using genetics, biochemistry, and high-resolution imaging, we found that antibiotic-induced protein transfer occurred between different strains of E. coli and between E. coli and other bacterial species. Furthermore, donor cells secreted transferrable protein into the supernatant as part of a larger complex. We traced donor supernatant transfer activity to a subset of membrane vesicles and found that these vesicles also contained PspA, a member of a highly conserved membrane-remodeling superfamily of proteins. PspA is expressed as part of the Psp membrane stress response, and the deletion of the Psp response from donors resulted in the loss of transfer vesicle production and donor transfer activity. Conversely, inducing the expression of the Psp response in recipients reduced the frequency of protein uptake, showing that the vesicle-producing and protein-receiving cell states are distinct. Through a combination of single-cell transcriptomics and genetics, we found that protein-receiving cells expressed high levels of a translation inhibitor that promotes antibiotic persistence, allowing cells to survive lethal doses of antibiotics. We further found that this translation inhibitor also promotes protein uptake by suppressing the Psp response. Finally, we demonstrated that uptake was associated with enhanced antibiotic survival, which suggests that vesicle-mediated horizontal protein transfer is an adjacent mechanism that supports antibiotic persistence in cells with reduced protein synthesis. CONCLUSION: This work shows direct evidence of membrane vesicle-mediated horizontal protein transfer between bacteria. Furthermore, it reveals that antibiotics stimulate the differentiation of bacteria into distinct groups of vesicle-producing and protein-receiving cells, which allows antibiotic persisters with decreased protein synthesis to acquire proteins secreted from active neighbors. New strategies to eliminate persisters could be developed by inhibiting or hijacking horizontal protein transfer. Tracking horizontal protein transfer with Cre-loxP.: Antibiotics stimulate horizontal protein transfer by promoting the differentiation of an isogenic population of bacteria into vesicle-producing donors and protein-receiving persisters. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | The exchange of biological matter between bacterial cells drives adaptation and evolution. However, whether bacteria can exchange functional proteins remains unclear. In this work, we found that antibiotic treatment can induce vesicle-mediated horizontal protein transfer within and between bacterial species. We developed a genetic system in Escherichia coli to track transfer events and performed single-cell transcriptomic profiling on an isogenic population of bacteria. Antibiotics stimulated the differentiation of this isogenic population into distinct cell states: donor cells that activated a membrane stress response to release protein-containing vesicles and recipient cells that suppressed this response to acquire protein from their neighbors. Protein uptake enhanced the antibiotic persistence of recipient cells, revealing that vesicle exchange promotes bacterial survival during antibiotic treatment. Editor's summary: In addition to killing bacteria, antibiotics can also promote adaptations that help bacteria survive. Wen et al. found that antibiotic stress triggers protein exchange between neighboring bacteria through membrane-bound vesicles (see the Perspective by Oms and Van Melderen). Some bacteria, especially dormant "persister" cells that normally turn off their protein synthesis, are more likely to take up these vesicles and use their contents to withstand antibiotic treatment. This process creates two transient cell states within an otherwise identical population: donor cells that release proteins and dormant recipient cells that receive them. By revealing how bacteria share proteins under antibiotic stress, this work uncovers a mechanism by which microbes can survive antibiotics and suggests potential strategies to target persistent infections. —Stella M. Hurtley INTRODUCTION: Bacterial cells exchange biological material, such as DNA and signaling molecules, to promote adaptation in stressful conditions, such as antibiotic exposure. Whereas horizontal gene transfer is known to spread antibiotic resistance genes, far less is understood about the mechanisms and effect of horizontal protein transfer. Bacterial membrane vesicles, which contain proteins, have been proposed as mediators of horizontal protein transfer. Additionally, antibiotic treatment stimulates vesicle production, suggesting a potential role for membrane vesicles in antibiotic survival. However, evidence for vesicle-mediated protein transfer remains indirect and correlative, which makes it difficult to rule out alternative mechanisms. To directly assess whether and how membrane vesicles contribute to protein transfer, a sensitive and specific method to detect transfer events is required. RATIONALE: To directly measure horizontal transfer, we constructed a genetic system in Escherichia coli consisting of a donor and a recipient strain. Donors express Cre recombinase, which activates a defective genetic marker in recipient cells, allowing individual transfer events to be detected. Using this approach, we tested whether antibiotics induce the transfer of Cre protein between cells and characterized the genetic and biochemical properties of the particles responsible. RESULTS: Using genetics, biochemistry, and high-resolution imaging, we found that antibiotic-induced protein transfer occurred between different strains of E. coli and between E. coli and other bacterial species. Furthermore, donor cells secreted transferrable protein into the supernatant as part of a larger complex. We traced donor supernatant transfer activity to a subset of membrane vesicles and found that these vesicles also contained PspA, a member of a highly conserved membrane-remodeling superfamily of proteins. PspA is expressed as part of the Psp membrane stress response, and the deletion of the Psp response from donors resulted in the loss of transfer vesicle production and donor transfer activity. Conversely, inducing the expression of the Psp response in recipients reduced the frequency of protein uptake, showing that the vesicle-producing and protein-receiving cell states are distinct. Through a combination of single-cell transcriptomics and genetics, we found that protein-receiving cells expressed high levels of a translation inhibitor that promotes antibiotic persistence, allowing cells to survive lethal doses of antibiotics. We further found that this translation inhibitor also promotes protein uptake by suppressing the Psp response. Finally, we demonstrated that uptake was associated with enhanced antibiotic survival, which suggests that vesicle-mediated horizontal protein transfer is an adjacent mechanism that supports antibiotic persistence in cells with reduced protein synthesis. CONCLUSION: This work shows direct evidence of membrane vesicle-mediated horizontal protein transfer between bacteria. Furthermore, it reveals that antibiotics stimulate the differentiation of bacteria into distinct groups of vesicle-producing and protein-receiving cells, which allows antibiotic persisters with decreased protein synthesis to acquire proteins secreted from active neighbors. New strategies to eliminate persisters could be developed by inhibiting or hijacking horizontal protein transfer. Tracking horizontal protein transfer with Cre-loxP.: Antibiotics stimulate horizontal protein transfer by promoting the differentiation of an isogenic population of bacteria into vesicle-producing donors and protein-receiving persisters. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adx3972 |
