Identification of Two Regulators of Virulence That Are Conserved in
            <i>Klebsiella pneumoniae</i>
            Classical and Hypervirulent Strains

Palacios, Michelle; Miner, Taryn A.; Frederick, Daniel R.; Sepúlveda, Victoria E.; Quinn, Joshua D.; Walker, Kimberly A.; Miller, Virginia L

doi:10.1128/mbio.01443-18

Cited by 73 publications

(94 citation statements)

References 87 publications

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“…RNA extraction and qRT-PCR analysis. RNA from overnight cultures of each K. pneumoniae strain was isolated and analyzed as previously described (66). Briefly, cultures were back diluted 1:50 in M9ϩglucose and grown at 37°C for 3 h in L media.…”

Section: Methodsmentioning

confidence: 99%

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Silver

Paczosa

McCabe

et al. 2019

Antimicrob Agents Chemother

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The emergence of multidrug-resistant Klebsiella pneumoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneumoniae survival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed and wild-type (WT) mice. The limited pool of amino acids in the lung did not change during infection and was insufficient for K. pneumoniae to overcome attenuating mutations in aroA, hisA, leuA, leuB, serA, serB, trpE, and tyrA in WT and immunosuppressed mice. Deletion of aroA, which encodes 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase class I, resulted in the most severe attenuation. Treatment with the EPSP synthase-specific competitive inhibitor glyphosate decreased K. pneumoniae growth in the lungs. K. pneumoniae expressing two previously identified glyphosate-resistant mutations in EPSP synthase had significant colonization defects in lung infection. Selection and characterization of six spontaneously glyphosate-resistant mutants in K. pneumoniae yielded no mutations in aroA. Strikingly, glyphosate treatment of mice lowered the bacterial burden of two of three spontaneous glyphosate-resistant mutants and further lowered the burden of the less-attenuated EPSP synthase catalytic mutant. Of 39 clinical isolate strains, 9 were resistant to glyphosate at levels comparable to those of selected resistant strains, and none appeared to be more highly resistant. These findings demonstrate amino acid biosynthetic pathways essential for K. pneumoniae infection are promising novel therapeutic targets.

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Section: Methodsmentioning

confidence: 99%

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Silver

Paczosa

McCabe

et al. 2019

Antimicrob Agents Chemother

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“…Newly described transcriptional regulators KvrA and KvrB also activate transcription of the chromosomal capsule synthesis genes and therefore are required for both full capsule production and HMV in hvKp strains. Accordingly, kvrA and kvrB deletion strains are less virulent than wild type .…”

Section: Defining Hvkp – Hypermucoviscositymentioning

confidence: 99%

Hypervirulent Klebsiella pneumoniae – clinical and molecular perspectives

2019

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Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a concerning global pathogen. hvKp is more virulent than classical K. pneumoniae (cKp) and capable of causing community‐acquired infections, often in healthy individuals. hvKp is carried in the gastrointestinal tract, which contributes to its spread in the community and healthcare settings. First recognized in Asia, hvKp arose as a leading cause of pyogenic liver abscesses. In the decades since, hvKp has spread globally and causes a variety of infections. In addition to liver abscesses, hvKp is distinct from cKp in its ability to metastasize to distant sites, including most commonly the eye, lung and central nervous system (CNS). hvKp has also been implicated in primary extrahepatic infections including bacteremia, pneumonia and soft tissue infections. The genetic determinants of hypervirulence are often found on large virulence plasmids as well as chromosomal mobile genetic elements which can be used as biomarkers to distinguish hvKp from cKp clinical isolates. These distinct virulence determinants of hvKp include up to four siderophore systems for iron acquisition, increased capsule production, K1 and K2 capsule types, and the colibactin toxin. Additionally, hvKp strains demonstrate hypermucoviscosity, a phenotypic description of hvKp in laboratory conditions that has become a distinguishing feature of many hypervirulent isolates. Alarmingly, multidrug‐resistant hypervirulent strains have emerged, creating a new challenge in combating this already dangerous pathogen.

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“…DhaR is a transcriptional activator responsible for controlling the production of the metabolic enzymes glycerol dehydrogenase and dihydroxyacetone kinase (18,19). KvrA is a MarR-type transcriptional repressor with a key role in K. pneumoniae capsulation (20–22).…”

Section: Textmentioning

confidence: 99%

“…Disruption of kvrA also causes downregulation of key capsule biosynthesis genes, e.g. galF , manC and wzi in some K. pneumoniae strains (20). We found using proteomics that Wzi was downregulated a marginal 0.82-fold ( p =0.03, n =3) upon disruption of kvrA in isolate S17 but not the GalF or ManC and none of these proteins were downregulated in FQ3Δ kvrA versus FQ3.…”

Section: Textmentioning

confidence: 99%

“…We found using proteomics that Wzi was downregulated a marginal 0.82-fold ( p =0.03, n =3) upon disruption of kvrA in isolate S17 but not the GalF or ManC and none of these proteins were downregulated in FQ3Δ kvrA versus FQ3. However, it is known that kvrA loss does not reduce capsule production is all strains, and nor does it attenuate the virulence of all strains in a mouse infection model (20). Among 455 isolates of K. pneumoniae from NCBI database, we found 9 isolates (Genbank accession numbers CP037927, LR134162, CP032175, CP018056, CP003200, LR588409, CP044039, CP043670, CP043669) where kvrA was mutated in a way predicted to result in a truncated and presumably non-functional KvrA.…”

Section: Textmentioning

confidence: 99%

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Mutation of kvrA causes OmpK35/36 porin downregulation and reduced meropenem/vaborbactam susceptibility in KPC-producing Klebsiella pneumoniae

Dulyayangkul

Ismah

Douglas

et al. 2019

Preprint

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AbstractMeropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK36 porin. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor that controls capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae clinical isolate.

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Identification of Two Regulators of Virulence That Are Conserved in Klebsiella pneumoniae Classical and Hypervirulent Strains

Cited by 73 publications

References 87 publications

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

Hypervirulent Klebsiella pneumoniae – clinical and molecular perspectives

Mutation of kvrA causes OmpK35/36 porin downregulation and reduced meropenem/vaborbactam susceptibility in KPC-producing Klebsiella pneumoniae

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