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Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant E. coli.

ABSTRACT:

Importance

Bacteria employ a number of mechanisms to adapt to antibiotics. Mutations in transcriptional regulators alter the expression levels of genes that can change the susceptibility of bacteria to antibiotics. Two-component signaling proteins are a major class of signaling molecule used by bacteria to regulate transcription. In previous work, we found that mutations in MgrB, a feedback regulator of the PhoQP two-component system, conferred trimethoprim tolerance to Escherichia coli. Here, we elucidate how mutations in MgrB have a domino-like effect on the gene regulatory network of E. coli. As a result, pervasive perturbation of gene regulation ensues. Depending on the environmental context, this pervasive deregulation is either adaptive or maladaptive. Our study sheds light on how deregulation of gene expression can be beneficial for bacteria when challenged with antibiotics, and why regulators like MgrB may have evolved in the first place.

SUBMITTER: Vinchhi R

PROVIDER: S-EPMC10746255 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant <i>E. coli</i>.

Vinchhi Rhea R Yelpure Chetna C Balachandran Manasvi M Matange Nishad N

mBio 20231130 6

<h4>Importance</h4>Bacteria employ a number of mechanisms to adapt to antibiotics. Mutations in transcriptional regulators alter the expression levels of genes that can change the susceptibility of bacteria to antibiotics. Two-component signaling proteins are a major class of signaling molecule used by bacteria to regulate transcription. In previous work, we found that mutations in MgrB, a feedback regulator of the PhoQP two-component system, conferred trimethoprim tolerance to <i>Escherichia co ...[more]

PMID: 38032208

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Project description:Urinary tract infections (UTIs) are the most common bacterial infections requiring medical attention and a leading justification for antibiotic prescription. Trimethoprim is prescribed empirically for uncomplicated cases. UTIs are primarily caused by extraintestinal pathogenic Escherichia coli (ExPEC) and ExPEC strains play a central role in disseminating antimicrobial-resistance genes worldwide. Here, we describe the whole-genome sequences of trimethoprim-resistant ExPEC and/or ExPEC from recurrent UTIs (67 in total) from patients attending a regional Australian hospital from 2006 to 2008. Twenty-three sequence types (STs) were observed, with ST131 predominating (28 %), then ST69 and ST73 (both 7 %). Co-occurrence of trimethoprim-resistance genes with genes conferring resistance to extended-spectrum β-lactams, heavy metals and quaternary ammonium ions was a feature of the ExPEC described here. Seven trimethoprim-resistance genes were identified, most commonly dfrA17 (38 %) and dfrA12 (18 %). An uncommon dfrB4 variant was also observed. Two blaCTX-M variants were identified - blaCTX-M-15 (16 %) and blaCTX-M-14 (10 %). The former was always associated with dfrA12, the latter with dfrA17, and all blaCTX-M genes co-occurred with chromate-resistance gene chrA. Eighteen class 1 integron structures were characterized, and chrA featured in eight structures; dfrA genes featured in seventeen. ST131 H30Rx isolates possessed distinct antimicrobial gene profiles comprising aac(3)-IIa, aac(6)-Ib-cr, aph(3')-Ia, aadA2, blaCTX-M-15, blaOXA-1 and dfrA12. The most common virulence-associated genes (VAGs) were fimH, fyuA, irp2 and sitA (all 91 %). Virulence profile clustering showed ST131 H30 isolates carried similar VAGs to ST73, ST405, ST550 and ST1193 isolates. The sole ST131 H27 isolate carried molecular predictors of enteroaggregative E. coli/ExPEC hybrid strains (aatA, aggR, fyuA). Seven isolates (10 %) carried VAGs suggesting ColV plasmid carriage. Finally, SNP analysis of serial UTI patients experiencing worsening sequelae demonstrated a high proportion of point mutations in virulence factors.

Project description:Although glutathione (GSH) has been shown to influence the antimicrobial effects of many kinds of antibiotics, little is known about its role in relation to trimethoprim (TMP), a widely used antifolate. In this study, several genes related to glutathione metabolism were deleted in different Escherichia coli strains (i.e., O157:H7 and ATCC 25922), and their effects on susceptibility to TMP were tested. The results showed that deleting gshA, gshB, grxA, and cydD caused TMP resistance, and deleting cydD also caused resistance to other drugs. Meanwhile, deleting gshA, grxA, and cydD resulted in a significant decrease of the periplasmic glutathione content. Supplementing exogenous GSH or further deleting glutathione importer genes (gsiB and ggt) restored TMP sensitivity to ΔcydD. Subsequently, the results of quantitative-reverse transcription PCR experiments showed that expression levels of acrA, acrB, and tolC were significantly upregulated in both ΔgrxA and ΔcydD. Correspondingly, deleting cydD led to a decreased accumulation of TMP within bacterial cells, and further deleting acrA, acrB, or tolC restored TMP sensitivity to ΔcydD. Inactivation of CpxR and SoxS, two transcriptional factors that modulate the transcription of acrAB-tolC, restored TMP sensitivity to ΔcydD. Furthermore, mutations of gshA, gshB, grxA, cydC, and cydD are highly prevalent in E. coli clinical strains. Collectively, these data suggest that reducing the periplasmic glutathione content of E. coli leads to increased expression of acrAB-tolC with the involvement of CpxR and SoxS, ultimately causing drug resistance. To the best of our knowledge, this is the first report showing a linkage between periplasmic GSH and drug resistance in bacteria. IMPORTANCE After being used extensively for decades, trimethoprim still remains one of the key accessible antimicrobials recommended by the World Health Organization. A better understanding of the mechanisms of resistance would be beneficial for the future utilization of this drug. It has been shown that the AcrAB-TolC efflux pump is associated with trimethoprim resistance in E. coli clinical strains. In this study, we show that E. coli can sense the periplasmic glutathione content with the involvement of the CpxAR two-component system. As a result, reducing the periplasmic glutathione content leads to increased expression of acrA, acrB, and tolC via CpxR and SoxS, causing resistance to antimicrobials, including trimethoprim. Meanwhile, mutations in the genes responsible for periplasmic glutathione content maintenance are highly prevalent in E. coli clinical isolates, indicating a potential correlation of the periplasmic glutathione content and clinical antimicrobial resistance, which merits further investigation.

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Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant E. coli.

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Publications

Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant <i>E. coli</i>.

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Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant E. coli.

Importance

Publications

Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant &lt;i&gt;E. coli&lt;/i&gt;.

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OmicsDI is part of the ELIXIR infrastructure

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Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant <i>E. coli</i>.