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Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks.

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Title: Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks.
Authors: Lubrano, Paul1,2,3 (AUTHOR), Smollich, Fabian1,2,3 (AUTHOR), Schramm, Thorben1,4 (AUTHOR), Lorenz, Elisabeth1 (AUTHOR), Alvarado, Alejandra1,2 (AUTHOR), Eigenmann, Seraina Carmen5 (AUTHOR), Stadelmann, Amelie1,2,3 (AUTHOR), Thavapalan, Sevvalli1,2,3 (AUTHOR), Waffenschmidt, Nils1 (AUTHOR), Glatter, Timo6 (AUTHOR), Hoffmann, Nadine2,7 (AUTHOR), Müller, Jennifer7,8 (AUTHOR), Peter, Silke2,7,8 (AUTHOR), Drescher, Knut5 (AUTHOR), Link, Hannes1,2,3 (AUTHOR) hannes.link@uni-tuebingen.de
Source: Molecular Systems Biology. Mar2025, Vol. 21 Issue 3, p274-293. 20p.
Subject Terms: *ESCHERICHIA coli, *BACTERIAL metabolism, *DRUG resistance in microorganisms, *DRUG resistance in bacteria, *CRISPRS
Abstract: Metabolic variation across pathogenic bacterial strains can impact their susceptibility to antibiotics and promote the evolution of antimicrobial resistance (AMR). However, little is known about how metabolic mutations influence metabolism and which pathways contribute to antibiotic susceptibility. Here, we measured the antibiotic susceptibility of 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. Across all mutants, we observed modest increases of the minimal inhibitory concentration (twofold to tenfold) without any cases of major resistance. Most mutants that showed reduced susceptibility to either of the two tested antibiotics carried mutations in metabolic genes. The effect of metabolic mutations on antibiotic susceptibility was antibiotic- and pathway-specific: mutations that reduced susceptibility against the β-lactam antibiotic carbenicillin converged on purine nucleotide biosynthesis, those against the aminoglycoside gentamicin converged on the respiratory chain. In addition, metabolic mutations conferred tolerance to carbenicillin by reducing growth rates. These results, along with evidence that metabolic bottlenecks are common among clinical E. coli isolates, highlight the contribution of metabolic mutations for AMR. Synopsis: A CRISPR screen and metabolomics reveal that metabolic mutations in E. coli create pathway-specific bottlenecks that reduce antibiotic susceptibility, demonstrating that bacterial metabolism plays a role in antimicrobial resistance and tolerance. A CRISPR library was screened against two antibiotics. Resistance mutations were enriched in metabolic genes. Metabolic mutations caused bottlenecks in their pathways. Clinical E. coli exhibited similar metabolic bottlenecks. A CRISPR screen and metabolomics reveal that metabolic mutations in E. coli create pathway-specific bottlenecks that reduce antibiotic susceptibility, demonstrating that bacterial metabolism plays a role in antimicrobial resistance and tolerance. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Systems Biology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks.
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  Data: Metabolic variation across pathogenic bacterial strains can impact their susceptibility to antibiotics and promote the evolution of antimicrobial resistance (AMR). However, little is known about how metabolic mutations influence metabolism and which pathways contribute to antibiotic susceptibility. Here, we measured the antibiotic susceptibility of 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. Across all mutants, we observed modest increases of the minimal inhibitory concentration (twofold to tenfold) without any cases of major resistance. Most mutants that showed reduced susceptibility to either of the two tested antibiotics carried mutations in metabolic genes. The effect of metabolic mutations on antibiotic susceptibility was antibiotic- and pathway-specific: mutations that reduced susceptibility against the β-lactam antibiotic carbenicillin converged on purine nucleotide biosynthesis, those against the aminoglycoside gentamicin converged on the respiratory chain. In addition, metabolic mutations conferred tolerance to carbenicillin by reducing growth rates. These results, along with evidence that metabolic bottlenecks are common among clinical E. coli isolates, highlight the contribution of metabolic mutations for AMR. Synopsis: A CRISPR screen and metabolomics reveal that metabolic mutations in E. coli create pathway-specific bottlenecks that reduce antibiotic susceptibility, demonstrating that bacterial metabolism plays a role in antimicrobial resistance and tolerance. A CRISPR library was screened against two antibiotics. Resistance mutations were enriched in metabolic genes. Metabolic mutations caused bottlenecks in their pathways. Clinical E. coli exhibited similar metabolic bottlenecks. A CRISPR screen and metabolomics reveal that metabolic mutations in E. coli create pathway-specific bottlenecks that reduce antibiotic susceptibility, demonstrating that bacterial metabolism plays a role in antimicrobial resistance and tolerance. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Molecular Systems Biology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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