Disarming Bacterial Virulence through Chemical Inhibition of the DNA Binding Domain of an AraC-like Transcriptional Activator Protein

Yang, Jiyeon; Hocking, Dianna M; Cheng, Catherine; Dogovski, Con; Perugini, Matthew A.; Holien, Jessica K.; Parker, Michael W.; Hartland, Elizabeth L.; Tauschek, Marija; Robins-Browne, Roy M.

doi:10.1074/jbc.m113.503912

Cited by 24 publications

(27 citation statements)

References 59 publications

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“…While this manuscript was in press, Yang et al [108] described an inhibitor targeting a T3SS-specific AraC family transcription factor in C. rodentium, RegA. This inhibitor, called regacin, inhibited the secretion of several C. rodentium T3SS substrates, including the effector Tir.…”

Section: Note Added In Proofmentioning

confidence: 92%

Targeting the type III secretion system to treat bacterial infections

Marshall

Finlay

2013

Expert Opinion on Therapeutic Targets

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Section: Note Added In Proofmentioning

confidence: 92%

Targeting the type III secretion system to treat bacterial infections

Marshall

Finlay

2013

Expert Opinion on Therapeutic Targets

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“…202 Newer antibiotics New antibiotic classes for which resistance is expected to be slow or difficult to develop are welcome arrivals. 203 Agents that suppress virulence characteristics, [204][205][206] rather than kill the microbe, should also select less strongly for resistance and are attractive candidates for co-administration with current antimicrobials, [207][208][209][210][211] although none is immediately available.…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications

Iredell

Brown

Tagg

2016

BMJ

289

177

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Resistance of the Enterobacteriaceae to antibiotics, especially of the β lactam type, is increasingly dominated by the mobilization of continuously expressed single genes that encode efficient drug modifying enzymes. Strong and ubiquitous selection pressure has seemingly been accompanied by a shift from "natural" resistance, such as inducible chromosomal enzymes, membrane impermeability, and drug efflux, to the modern paradigm of mobile gene pools that largely determine the epidemiology of modern antibiotic resistance. In this way, antibiotic resistance is more available than ever before to organisms such as Escherichia coli and Klebsiella pneumoniae that are important causes of major sepsis. Modulation of the phenotype by host bacteria makes gene transmission less obvious and may in part explain why tracking and control of carbapenem resistance has been particularly problematic in the Enterobacteriaceae. This review discusses the underlying principles and clinical implications of the mobility and fixation of resistance genes and the exploitable opportunities and potential threats arising from apparent limitations on diversity in these mobile gene pools. It also provides some illustrative paradoxes and clinical corollaries, as well as a summary of future options.

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“…A high-throughput screening system similar to that described by Yang et al (52) has been established, and experiments are under way to identify small-molecule inhibitors of the MrkH protein from a commercial chemical library.…”

Section: Figmentioning

confidence: 99%

Positive Autoregulation ofmrkHIby the Cyclic Di-GMP-Dependent MrkH Protein in the Biofilm Regulatory Circuit of Klebsiella pneumoniae

Tan¹,

Wilksch²,

Hocking³

et al. 2015

J. Bacteriol.

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Klebsiella pneumoniae is an important cause of nosocomial infections, primarily through the formation of surface-associated biofilms to promote microbial colonization on host tissues. Expression of type 3 fimbriae by K. pneumoniae facilitates surface adherence, a process strongly activated by the cyclic di-GMP (c-di-GMP)-dependent transcriptional activator MrkH. In this study, we demonstrated the critical importance of MrkH in facilitating K. pneumoniae attachment on a variety of medically relevant materials and demonstrated the mechanism by which bacteria activate expression of type 3 fimbriae to colonize these materials. Sequence analysis revealed a putative MrkH recognition DNA sequence ("MrkH box"; TATCAA) located in the regulatory region of the mrkHI operon. Mutational analysis, electrophoretic mobility shift assay, and quantitative PCR experiments demonstrated that MrkH binds to the cognate DNA sequence to autoregulate mrkHI expression in a c-di-GMP-dependent manner. A half-turn deletion, but not a full-turn deletion, between the MrkH box and the ؊35 promoter element rendered MrkH ineffective in activating mrkHI expression, implying that a direct interaction between MrkH and RNA polymerase exists. In vivo analyses showed that residues L260, R265, N268, C269, E273, and I275 in the C-terminal domain of the RNA polymerase ␣ subunit are involved in the positive control of mrkHI expression by MrkH and revealed the regions of MrkH required for DNA binding and transcriptional activation. Taken together, the data suggest a model whereby c-di-GMP-dependent MrkH recruits RNA polymerase to the mrkHI promoter to autoactivate mrkH expression. Increased MrkH production subsequently drives mrkABCDF expression when activated by c-di-GMP, leading to biosynthesis of type 3 fimbriae and biofilm formation. IMPORTANCEBacterial biofilms can cause persistent infections that are refractory to antimicrobial treatments. This study investigated how a commonly encountered hospital-acquired pathogen, Klebsiella pneumoniae, controls the expression of MrkH, the principal regulator of type 3 fimbriae and biofilm formation. We discovered a regulatory circuit whereby MrkH acts as a c-di-GMP-dependent transcriptional activator of both the gene cluster of type 3 fimbriae and the mrkHI operon. In this positive-feedback loop, whereby MrkH activates its own production, K. pneumoniae has evolved a mechanism to ensure rapid MrkH production, expression of type 3 fimbriae, and subsequent biofilm formation under favorable conditions. Deciphering the molecular mechanisms of biofilm formation by bacterial pathogens is important for the development of innovative treatment strategies for biofilm infections. Biofilm-related infections substantially contribute to patient morbidity and place a significant burden on health care systems. The evolution of high-technology medicine such as intensive and invasive hospital care practices and immunosuppressive therapy and the emergence of multiply antibiotic-resistant organisms have contributed to the rise...

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Disarming Bacterial Virulence through Chemical Inhibition of the DNA Binding Domain of an AraC-like Transcriptional Activator Protein

Cited by 24 publications

References 59 publications

Targeting the type III secretion system to treat bacterial infections

Targeting the type III secretion system to treat bacterial infections

Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications

Positive Autoregulation ofmrkHIby the Cyclic Di-GMP-Dependent MrkH Protein in the Biofilm Regulatory Circuit of Klebsiella pneumoniae

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