Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

ABSTRACT: The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Jin Feng

PROVIDER: PXD053342 | iProX | Mon Jun 24 00:00:00 BST 2024

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Similar Datasets

A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

Project description:<p>The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC) and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.</p>

2024-07-03 | MTBLS10516 | MetaboLights

Molecular Responses During Bacterial Filamentation Induced by Antibiotics

Project description:Bacterial filamentation is one of the most important bacterial SOS responses to antibiotic drugs and contributes to the development of antimicrobial resistance. Understanding the mechanism of the bacterial SOS response is crucial to control the development of antibiotic-resistant bacteria. We uncover the molecular changes of SOS-associated bacterial filamentation. Bacterial proteins that correlate with bacterial SOS responses and facilitate to bacterial antimicrobial resistance are studied.

2023-01-04 | PXD039235 | iProX

A new antibiotic from an uncultured bacterium binds to an immutable target

Project description:Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positivebacterial pathogens without detectable resistance. Using biochemical assays,solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, Lipid II, LipidWTA). Clovibactin uses anunusual hydrophobic interface to tightly wrap aroundpyrophosphate, butbypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups.Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.

2023-08-22 | GSE228489 | GEO

Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds [HDFa]

Project description:The management of antibiotic-resistant, bacterial biofilm infections in chronic skin wounds is a significant clinical challenge. Despite advances in diagnosis, many patients do not derive benefit from current anti-infective/antibiotic therapies. Here we report a novel class of epoxy-tiglianes and demonstrate their antimicrobial activity (modifying bacterial growth and inducing biofilm disruption), with structure/activity relationships established against important human pathogens. In vitro, the lead candidate, EBC-1013 stimulated PKC-dependent neutrophil ROS induction and NETosis, and increased expression of wound healing associated cytokines, chemokines and antimicrobial peptides in keratinocytes and fibroblasts. In vivo, topical EBC-1013 induced rapid resolution of infection with increased matrix remodelling in acute thermal injuries. In chronically-infected, diabetic wounds, treatment induced cytokine/chemokine production, inflammatory cell recruitment and complete healing (in 6/7 wounds) with ordered keratinocyte differentiation. These results highlight a non-antibiotic approach involving contrasting, orthogonal mechanisms of action: targeted biofilm disruption and innate immune induction in the treatment of chronic wounds.

2022-05-14 | GSE202952 | GEO

Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds [HEKa]

2022-05-12 | GSE202794 | GEO

The ‘PepSAVI-MS’ pipeline for natural product bioactive peptide discovery

Project description:The recent increase in extensively drug resistant bacterial pathogens and the associated increase of morbidity and mortality demonstrate the immediate need for new antibiotic backbones with novel mechanisms of action. Here, we report the development of the PepSAVI-MS pipeline for bioactive peptide discovery. This highly versatile platform employs bioinformatics, statistics, and mass spectrometry to identify bioactive peptide targets from complex biological samples. We validate the use of this platform through the successful identification of known bioactive peptides from a botanical species, Viola odorata. Using this pipeline, we have widened the known antimicrobial spectrum for V. odorata cyclotides, including antibacterial activity of cycloviolacin O2 against E. faecium and A. baumannii. We further demonstrate the broad applicability of the platform through the identification of novel anticancer activities for cycloviolacins by their cytotoxicity against ovarian, breast and prostate cancer cell lines.

2017-01-02 | PXD004780 | Pride

Rahman2022 - High throughput antibacterial screening with machine learning.

Project description:Prediction of antimicrobial potential using a dataset of 29537 compounds screened against the antibiotic resistant pathogen Burkholderia cenocepacia. The model uses the Chemprop Direct Message Passing Neural Network (D-MPNN) and has an AUC score of 0.823 for the test set. It has been used to virtually screen the FDA approved drugs as well as a collection of natural product list (>200k compounds) with hit rates of 26% and 12% respectively. Model Type: Predictive machine learning model. Model Relevance: Probability that a compound inhibits bacterial pathogens with a focus on ESKAPE. Model Encoded by: Sarima Chiorlu (Ersilia) Metadata Submitted in BioModels by: Zainab Ashimiyu-Abdusalam Implementation of this model code by Ersilia is available here: https://github.com/ersilia-os/eos5xng

2024-04-22 | MODEL2404080002 | BioModels

Collateral sensitivity of antibiotic resistant bacteria to antimicrobial peptides

Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.

2018-03-29 | GSE96706 | GEO

Discovery and characterization of the antimetabolite action of thioacetamide-linked 1,2,3-triazoles as disruptors of cysteine biosynthesis in Gram-negative bacteria

Project description:Increasing rates of drug-resistant Gram-negative (GN) infections combined with a lack of new GN-effective antibiotic classes is driving the need for the discovery of new agents. As bacterial metabolism represents an underutilized mechanism targeted in current antimicrobial therapies, we sought to identify novel antimetabolites and explore the specific impacts of these inhibitors on key pathways in bacterial metabolism. This study describes the successful application of this approach to discover N-(phenyl) thioacetamide-linked 1,2,3-triazoles (TAT) that target cysteine synthase A (CysK), an enzyme unique to bacteria that is positioned at a key juncture between several fundamental pathways. The TAT class was identified using a high-throughput screen against Escherichia coli designed to identify modulators of pathways related to folate biosynthesis. TAT analog synthesis revealed a clear structure-activity relationship, and activity was confirmed against GN antifolate-resistant clinical isolates. Spontaneous TAT resistance mutations were tracked to CysK, and mode of action studies led to the identification of a false product formation mechanism between the CysK substrate O-acetyl-L-serine and the TATs. Global transcriptional responses to TAT treatment revealed that these antimetabolites impose substantial disruption of key metabolic networks beyond cysteine biosynthesis. This study highlights the potential of antimetabolite drug discovery as a promising approach to the discovery of novel GN antibiotics.

2020-01-01 | GSE142164 | GEO

Proteomic analysis of anti-MRSA activity of caerin 1.1/1.9 in a murine skin infection model

Project description:Caerin 1 is a family of host-defense peptides with antimicrobial property originally isolated from Australia tree frog. Caerin 1.1+1.9 has been shown to inhibit multiple antibiotic resistant bacteria infection both in vitro and in vivo. In current study, we compare the MICs of caerin 1.1/1.9 with commonly used antibiotics against S. aureus, Copper-Green Pseudomonas aeruginosa, Acinetobacter baumannii, and Streptococcus haemolyticus. We demonstrate that caerin 1.1/1.9 not only prevent the formation of biofilm by A. Baumann, but also have therapeutic effect on established biofilm. In addition, we find that caerin1.1/1.9 significantly inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) strain in a murine skin infection model. The quantitative proteomic analysis suggested that caerin1.1/1.9 largely activate oxidative phosphorylation, as well as several pathways associated with tissue repair and growth, with respect to the untreated tissues infected with MRSA in mice. In summary, our results suggest that caerin 1.1/1.9 have the potential to be used as a drug candidate treating complicated antibiotic resistant bacterial infection in human.

2023-10-11 | PXD044425 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data