Bacterial response to TAT-RasGAP 317-326 antimicrobial peptide
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB45735 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6124700.fastq.gz | Fastqsanger.gz | |||
| ERR6124830_1.fastq.gz | Fastqsanger.gz | |||
| ERR6124830_2.fastq.gz | Fastqsanger.gz | |||
| ERR6124691.fastq.gz | Fastqsanger.gz | |||
| ERR6124693.fastq.gz | Fastqsanger.gz |
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Project description:Antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics against multidrug resistant pathogens. TAT-RasGAP (317-326) is an AMP with broad range antibacterial activity, but its mechanism of action is unknown. Escherichia coli can become partially resistant to TAT-RasGAP (317-326) in vitro when passaged eight times with increasing concentrations of this peptide via mutations of the two-component system EnvZ/OmpR. To test whether additional mutations can cause further increase in resistance, we analysed a strain of E. coli showing high level of specific resistance to TAT-RasGAP (317-326) that we obtained after twenty passages of in vitro resistance selection. This strain bears, in addition to an envZ point mutation, a point mutation in bamA, an essential gene encoding an insertase involved in the insertion of outer membrane proteins. This mutation modifies the charge in a negatively charged loop (Q495-T505) at the surface of BamA. In silico docking simulations predict that binding affinity between TAT-RasGAP (317-326) and BamA varies depending on the charge of the Q495-T505 loop. We show here using CRISPR-Cas9-based targeted mutagenesis that mutations lowering the negative charge of the Q495-T505 loop decrease sensitivity of E. coli to TAT-RasGAP (317-326). Interestingly, BamA activity was not affected by TAT-RasGAP (317-326), indicating that BamA may function as a specific receptor for the AMP TAT-RasGAP (317-326). Our results indicate that binding and entry of TAT-RasGAP (317-326) may involve different mechanisms compared to other AMPs, which is in line with limited cross-resistance observed between different AMPs. This limited cross-resistance is important for the clinical application of AMPs towards multidrug resistant pathogens.
2024-12-02 | PXD051962 | Pride
Project description:Antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics against antibiotic-resistant pathogens. TAT-RasGAP (317-326) is an AMP with broad range antibacterial activity, but its mechanism of action is unknown. Escherichia coli can become partially resistant to TAT-RasGAP (317-326) in vitro. In this study, we analysed a strain of E. coli with extensive resistance to TAT-RasGAP (317-326) but not to other AMPs that we obtained after twenty passages during an in vitro resistance selection experiment. This strain accumulates four mutations, that all apparently affect bacterial envelope composition. One of these mutations is a point mutation in bamA, which encodes an essential protein involved in the folding and proper insertion of outer membrane proteins. The point mutation resulted in a charge change in an area of the protein corresponding to a negatively charged loop at the surface of BamA. Using CRISPR-Cas9-based targeted mutagenesis, we showed that mutations lowering the negative charge of this loop decreased sensitivity of E. coli to TAT-RasGAP (317-326). In silico simulations unveiled the molecular driving forces responsible for the interaction between TAT-RasGAP (317-326) and BamA. These results indicated that electrostatic interactions, particularly hydrogen bonds, are involved in the stability of the molecular complex, representing a predictive fingerprint of the TAT-RasGAP (317-326) - BamA interaction strength. Interestingly, BamA activity was not affected by TAT-RasGAP (317-326), indicating that BamA may function as a specific receptor for this AMP. Our results indicate that binding and entry of TAT-RasGAP (317-326) may involve different mechanisms compared to other AMPs, which is in line with limited cross-resistance observed between different AMPs. This limited cross-resistance is important for the clinical application of AMPs towards drug-resistant pathogens.
2024-12-02 | PXD055766 | Pride
Project description:Antibiotic resistance is an increasing threat for public health, underscoring the need for new antibacterial agents. Antimicrobial peptides (AMPs) represent an alternative to classical antibiotics. TAT-RasGAP317-326 is a recently described AMP effective against a broad range of bacteria, but little is known about the conditions that may influence its activity. Using RNA-sequencing and screening of mutant libraries, we show that Escherichia coli and Pseudomonas aeruginosa respond to TAT-RasGAP317-326 by regulating metabolic and stress response pathways, possibly implicating two-component systems. Our results also indicate that bacterial surface properties, in particular integrity of the lipopolysaccharide layer, influence peptide binding and entry. Finally, we found differences between bacterial species with respect to their rate of resistance emergence against this peptide. Our findings provide the basis for future investigation on the mode of action of TAT-RasGAP317-326, which may help developing antimicrobial treatments based on this peptide.
| S-EPMC8365389 | biostudies-literature
Project description:Antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics against antibiotic-resistant pathogens. TAT-RasGAP317-326 is an AMP with broad range antibacterial activity, but its mechanism of action is unknown. In this study, we analyzed a strain of Escherichia coli with extensive resistance to TAT-RasGAP317-326 but not to other AMPs that we obtained after twenty passages during an in vitro resistance selection experiment. This strain accumulated four mutations. One of these is a point mutation in bamA, which encodes an essential protein involved in the folding and proper insertion of outer membrane proteins. The mutation resulted in a change of charge in a surface-exposed negatively charged loop of the BamA protein. Using CRISPR-Cas9-based targeted mutagenesis, we showed that mutations lowering the negative charge of this loop decreased sensitivity of E. coli to TAT-RasGAP317-326. In silico simulations unveiled the molecular driving forces responsible for the interaction between TAT-RasGAP317-326 and BamA. These results indicated that electrostatic interactions, particularly hydrogen bonds, are involved in the stability of the molecular complex, representing a predictive fingerprint of the TAT-RasGAP317-326 - BamA interaction strength. Interestingly, BamA activity was only partially affected by TAT-RasGAP317-326, indicating that BamA may function as a specific receptor for this AMP. Our results indicate that binding and entry of TAT-RasGAP317-326 may involve different mechanisms compared to other AMPs, which is in line with limited cross-resistance observed between different AMPs. This limited cross-resistance is important for the clinical application of AMPs towards drug-resistant pathogens.
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Project description:TAT-RasGAP317-326 is a cell-penetrating peptide-based construct with anticancer and antimicrobial activities. This peptide kills a subset of cancer cells in a manner that does not involve known programmed cell death pathways. Here we have elucidated the mode of action allowing TAT-RasGAP317-326 to kill cells. This peptide binds and disrupts artificial membranes containing lipids typically enriched in the inner leaflet of the plasma membrane, such as phosphatidylinositol-bisphosphate (PIP2) and phosphatidylserine (PS). Decreasing the amounts of PIP2 in cells renders them more resistant to TAT-RasGAP317-326, while reducing the ability of cells to repair their plasma membrane makes them more sensitive to the peptide. The W317A TAT-RasGAP317-326 point mutant, known to have impaired killing activities, has reduced abilities to bind and permeabilize PIP2- and PS-containing membranes and to translocate through biomembranes, presumably because of a higher propensity to adopt an α-helical state. This work shows that TAT-RasGAP317-326 kills cells via a form of necrosis that relies on the physical disruption of the plasma membrane once the peptide targets specific phospholipids found on the cytosolic side of the plasma membrane.
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