Merging multi-omics with proteome integral solubility alteration unveils antibiotic mode of action

• Published in: eLife Vol. 13
• Main Authors: Maity, Ritwik, Zhang, Xuepei, Liberati, Francesca Romana, Scribani Rossi, Chiara, Cutruzzolá, Francesca, Rinaldo, Serena, Gaetani, Massimiliano, Aínsa, José Antonio, Sancho, Javier
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27.09.2024
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Antimicrobial agents; Antimicrobial resistance; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biosynthesis; CagA; Drug development; Drug resistance; FtsZ; Genes; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - genetics; Helicobacter pylori - metabolism; Medicin och hälsovetenskap; Metabolism; Molecular modelling; multi-omics; Multiomics; Ontology; Pathogenicity; Pathogens; Proteins; Proteome - metabolism; Proteomes; Proteomics; Proteomics - methods; Solubility; target deconvolution; computational biology; systems biology; target deconvolution; FtsZ; Helicobacter pylori; antimicrobial resistance; infectious disease; CagA; microbiology; multi-omics
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.96343

Antimicrobial resistance is responsible for an alarming number of deaths, estimated at 5 million per year. To combat priority pathogens, like , the development of novel therapies is of utmost importance. Understanding the molecular alterations induced by medications is critical for the design of multi-targeting treatments capable of eradicating the infection and mitigating its pathogenicity. However, the application of bulk omics approaches for unraveling drug molecular mechanisms of action is limited by their inability to discriminate between target-specific modifications and off-target effects. This study introduces a multi-omics method to overcome the existing limitation. For the first time, the Proteome Integral Solubility Alteration (PISA) assay is utilized in bacteria in the PISA-Express format to link proteome solubility with different and potentially immediate responses to drug treatment, enabling us the resolution to understand target-specific modifications and off-target effects. This study introduces a comprehensive method for understanding drug mechanisms and optimizing the development of multi-targeting antimicrobial therapies.