Dataset Information

Coordinated regulation of acid resistance in Escherichia coli.

ABSTRACT: BACKGROUND:Enteric Escherichia coli survives the highly acidic environment of the stomach through multiple acid resistance (AR) mechanisms. The most effective system, AR2, decarboxylates externally-derived glutamate to remove cytoplasmic protons and excrete GABA. The first described system, AR1, does not require an external amino acid. Its mechanism has not been determined. The regulation of the multiple AR systems and their coordination with broader cellular metabolism has not been fully explored. RESULTS:We utilized a combination of ChIP-Seq and gene expression analysis to experimentally map the regulatory interactions of four TFs: nac, ntrC, ompR, and csiR. Our data identified all previously in vivo confirmed direct interactions and revealed several others previously inferred from gene expression data. Our data demonstrate that nac and csiR directly modulate AR, and leads to a regulatory network model in which all four TFs participate in coordinating acid resistance, glutamate metabolism, and nitrogen metabolism. This model predicts a novel mechanism for AR1 by which the decarboxylation enzymes of AR2 are used with internally derived glutamate. This hypothesis makes several testable predictions that we confirmed experimentally. CONCLUSIONS:Our data suggest that the regulatory network underlying AR is complex and deeply interconnected with the regulation of GABA and glutamate metabolism, nitrogen metabolism. These connections underlie and experimentally validated model of AR1 in which the decarboxylation enzymes of AR2 are used with internally derived glutamate.

SUBMITTER: Aquino P

PROVIDER: S-EPMC5217608 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Coordinated regulation of acid resistance in Escherichia coli.

Aquino Patricia P Honda Brent B Jaini Suma S Lyubetskaya Anna A Hosur Krutika K Chiu Joanna G JG Ekladious Iriny I Hu Dongjian D Jin Lin L Sayeg Marianna K MK Stettner Arion I AI Wang Julia J Wong Brandon G BG Wong Winnie S WS Alexander Stephen L SL Ba Cong C Bensussen Seth I SI Bernstein David B DB Braff Dana D Cha Susie S Cheng Daniel I DI Cho Jang Hwan JH Chou Kenny K Chuang James J Gastler Daniel E DE Grasso Daniel J DJ Greifenberger John S JS Guo Chen C Hawes Anna K AK Israni Divya V DV Jain Saloni R SR Kim Jessica J Lei Junyu J Li Hao H Li David D Li Qian Q Mancuso Christopher P CP Mao Ning N Masud Salwa F SF Meisel Cari L CL Mi Jing J Nykyforchyn Christine S CS Park Minhee M Peterson Hannah M HM Ramirez Alfred K AK Reynolds Daniel S DS Rim Nae Gyune NG Saffie Jared C JC Su Hang H Su Wendell R WR Su Yaqing Y Sun Meng M Thommes Meghan M MM Tu Tao T Varongchayakul Nitinun N Wagner Tyler E TE Weinberg Benjamin H BH Yang Rouhui R Yaroslavsky Anastasia A Yoon Christine C Zhao Yanyu Y Zollinger Alicia J AJ Stringer Anne M AM Foster John W JW Wade Joseph J Raman Sahadaven S Broude Natasha N Wong Wilson W WW Galagan James E JE

BMC systems biology 20170106 1

<h4>Background</h4>Enteric Escherichia coli survives the highly acidic environment of the stomach through multiple acid resistance (AR) mechanisms. The most effective system, AR2, decarboxylates externally-derived glutamate to remove cytoplasmic protons and excrete GABA. The first described system, AR1, does not require an external amino acid. Its mechanism has not been determined. The regulation of the multiple AR systems and their coordination with broader cellular metabolism has not been full ...[more]

PMID: 28061857

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Project description:Benzoic acid, a partial uncoupler of the proton motive force (PMF), selects for sensitivity to chloramphenicol and tetracycline during the experimental evolution of Escherichia coli K-12. Transcriptomes of E. coli isolates evolved with benzoate showed the reversal of benzoate-dependent regulation, including the downregulation of multidrug efflux pump genes, the gene for the Gad acid resistance regulon, the nitrate reductase genes narHJ, and the gene for the acid-consuming hydrogenase Hyd-3. However, the benzoate-evolved strains had increased expression of OmpF and other large-hole porins that admit fermentable substrates and antibiotics. Candidate genes identified from benzoate-evolved strains were tested for their roles in benzoate tolerance and in chloramphenicol sensitivity. Benzoate or salicylate tolerance was increased by deletion of the Gad activator ariR or of the acid fitness island from slp to the end of the gadX gene encoding Gad regulators and the multidrug pump genes mdtEF Benzoate tolerance was also increased by deletion of multidrug component gene emrA, RpoS posttranscriptional regulator gene cspC, adenosine deaminase gene add, hydrogenase gene hyc (Hyd-3), and the RNA chaperone/DNA-binding regulator gene hfq Chloramphenicol resistance was decreased by mutations in genes for global regulators, such as RNA polymerase alpha subunit gene rpoA, the Mar activator gene rob, and hfq Deletion of lipopolysaccharide biosynthetic kinase gene rfaY decreased the rate of growth in chloramphenicol. Isolates from experimental evolution with benzoate had many mutations affecting aromatic biosynthesis and catabolism, such as aroF (encoding tyrosine biosynthesis) and apt (encoding adenine phosphoribosyltransferase). Overall, benzoate or salicylate exposure selects for the loss of multidrug efflux pumps and of hydrogenases that generate a futile cycle of PMF and upregulates porins that admit fermentable nutrients and antibiotics.IMPORTANCE Benzoic acid is a common food preservative, and salicylic acid (2-hydroxybenzoic acid) is the active form of aspirin. At high concentrations, benzoic acid conducts a proton across the membrane, depleting the proton motive force. In the absence of antibiotics, benzoate exposure selects against proton-driven multidrug efflux pumps and upregulates porins that admit fermentable substrates but that also allow the entry of antibiotics. Thus, evolution with benzoate and related molecules, such as salicylates, requires a trade-off for antibiotic sensitivity, a trade-off that could help define a stable gut microbiome. Benzoate and salicylate are naturally occurring plant signal molecules that may modulate the microbiomes of plants and animal digestive tracts so as to favor fermenters and exclude drug-resistant pathogens.

Dataset Information

Coordinated regulation of acid resistance in Escherichia coli.

Publications

Coordinated regulation of acid resistance in Escherichia coli.

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