A dual-mechanism antimicrobial peptide with antimutagenic activity targets the replisome and induces cell envelope stress
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ABSTRACT:
PROVIDER: PRJNA1156165 | ENA |
REPOSITORIES: ENA
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Project description:To combat the growing threat of multidrug-resistant bacteria, we need to develop novel antibiotics with unique modes of action. This study investigates the antibacterial properties of BTP-001 towards Escherichia coli. BTP-001 is a β-clamp targeting antimicrobial peptide containing an AlkB homologu 2 PCNA-interacting motif (APIM) linked to a cell penetrating peptide composed of 11 arginine residues (R11). Our data indicates that R11 mediates energy-dependent transport of BTP-001 across the cell membrane, possibly via iron transport systems such as the TonB-system. The full-length BTP-001 peptide rapidly affects the bacterial membrane, inducing increased expression and activation of the Cpx, E and Rcs cell envelope stress responses, which trigger the production of reaction oxygen species (ROS). This contributes to a rapid bactericidal effect as evidenced by increased short-term survival by addition of a ROS scavenger. Furthermore, we show that BTP-001 reduces the development of resistance to ciprofloxacin likely by binding to the β-clamp via APIM, thereby inhibiting translesion synthesis. In addition, our multi-omics data suggests that the -clamp is part of ribosomal complexes, and that regulation of translation is targeted by BTP-001. In conclusion, BTP-001 exhibits a multifaceted mode of action which strengthens its potential as a novel therapeutic drug against antibiotic resistant bacteria
2025-08-25 | GSE276254 | GEO
Project description:To combat the growing threat of multidrug-resistant bacteria, we need to develop novel antibiotics with unique modes of action. This study investigates the antibacterial properties of BTP-001 towards Escherichia coli. BTP-001 is a β-clamp targeting antimicrobial peptide containing an AlkB homologu 2 PCNA-interacting motif (APIM) linked to a cell penetrating peptide composed of 11 arginine residues (R11). Our data indicates that R11 mediates energy-dependent transport of BTP-001 across the cell membrane, possibly via iron transport systems such as the TonB-system. The full-length BTP-001 peptide rapidly affects the bacterial membrane, inducing increased expression and activation of the Cpx, E and Rcs cell envelope stress responses, which trigger the production of reaction oxygen species (ROS). This contributes to a rapid bactericidal effect as evidenced by increased short-term survival by addition of a ROS scavenger. Furthermore, we show that BTP-001 reduces the development of resistance to ciprofloxacin likely by binding to the β-clamp via APIM, thereby inhibiting translesion synthesis. In addition, our multi-omics data suggests that the -clamp is part of ribosomal complexes, and that regulation of translation is targeted by BTP-001. In conclusion, BTP-001 exhibits a multifaceted mode of action which strengthens its potential as a novel therapeutic drug against antibiotic resistant bacteria.
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Project description:Staphylococcus aureus is a leading cause of hospital-associated infections. In addition, highly virulent strains of methicillin-resistant S. aureus (MRSA) are currently spreading outside health care settings. Survival in the human host is largely defined by the ability of S. aureus to resist mechanisms of innate host defense, of which antimicrobial peptides form a key part especially on epithelia and in neutrophil phagosomes. Here we demonstrate that the antimicrobial-peptide sensing system aps of the standard community-associated MRSA strain MW2 controls resistance to cationic antimicrobial peptides. The core of aps-controlled resistance mechanisms comprised the D-alanylation of teichoic acids (dlt operon), the incorporation of cationic lysyl-phosphatidylglycerol (L-PG) in the bacterial membrane (mprF), and the vraF/vraG putative antimicrobial peptide transporter. Further, the observed increased production of L-PG under the influence of cationic antimicrobial peptides was accompanied by the up-regulation of lysine biosynthesis. In noticeable difference to the aps system of S. epidermidis, only selected antimicrobial peptides strongly induced the aps response. Heterologous complementation with the S. epidermidis apsS gene indicated that this is likely caused by differences in the short extracellular loop of ApsS that interacts with the inducing antimicrobial peptide. Our study shows that the antimicrobial peptide sensor system aps is functional in the important human pathogen S. aureus, significant interspecies differences exist in the induction of the aps gene regulatory response, and aps inducibility is clearly distinguishable from effectiveness towards a given antimicrobial peptide. Keywords: Wild type control vs treated vs mutant Wild type untreated in triplicate is compared to wild type treated in triplicate along with three mutants in triplicate with and without treatment of indolicidin, totalling 30 samples
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2014-08-01 | E-GEOD-49472 | biostudies-arrayexpress
Project description:To survive during colonization or infection of the human body, microorganisms must defeat antimicrobial peptides, which represent a key component of innate host defense in phagocytes and on epithelia. However, is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms to antimicrobial peptides and is unrelated to the Gram-negative PhoP/PhoQ system. Wild type untreated in triplicate is compared to wild type treated in triplicate along with three mutants in triplicate with and without treatment of human beta defensin 3, totalling 30 samples
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Project description:To survive during colonization or infection of the human body, microorganisms must defeat antimicrobial peptides, which represent a key component of innate host defense in phagocytes and on epithelia. However, is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms to antimicrobial peptides and is unrelated to the Gram-negative PhoP/PhoQ system. Keywords: Wild type control vs treated vs mutant
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Project description:Peptides have great potential to combat antibiotic resistance. While many platforms can screen peptides for their ability to bind to target cells, there are virtually no platforms that directly assess the functionality of peptides. This limitation is exacerbated when identifying antimicrobial peptides, since the phenotype, death, selects against itself, and has caused a scientific bottleneck confining research to only a few naturally occurring classes of antimicrobial peptides. We have used this seeming dissonance to develop Surface Localized Antimicrobial displaY (SLAY); a platform that allows screening of unlimited numbers of peptides of any length, composition, and structure in a single tube for antimicrobial activity. Using SLAY, we screened ~800,000 random peptide sequences for antimicrobial function and identified thousands of active sequences doubling the number of known antimicrobial sequences. SLAY hits present with different potential mechanisms of peptide action and access to areas of antimicrobial physicochemical space beyond what nature has evolved.
2018-01-03 | GSE94530 | GEO
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