Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay

Bohnert, Jürgen A.; Schuster, Sabine; Kern, Winfried V.; Karcz, Tadeusz; Olejarz, Agnieszka; Kaczor, Aneta; Handzlik, Jadwiga; Kieć‐Kononowicz, Katarzyna

doi:10.1128/aac.01995-15

Cited by 36 publications

(30 citation statements)

References 25 publications

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“…The amphiphilic nature of the Generation IIIA of optimized derivatives seems to be crucial to inhibit antibiotic resistance mediated by efflux pump and open new ways for generating original active compounds able to inhibit pump activity. With the recent published data regarding piperazine arylideneimidazolone derivatives as potential efflux inhibitors in Escherichia coli cells ( Bohnert et al, 2016 ), the compound 32 characterized in this study will be used for pharmacophoric modulations in order to develop more potent inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Efflux Pump Blockers in Gram-Negative Bacteria: The New Generation of Hydantoin Based-Modulators to Improve Antibiotic Activity

et al. 2016

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Multidrug resistant (MDR) bacteria are an increasing health problem with the shortage of new active antibiotic agents. Among effective mechanisms that contribute to the spread of MDR Gram-negative bacteria are drug efflux pumps that expel clinically important antibiotic classes out of the cell. Drug pumps are attractive targets to restore the susceptibility toward the expelled antibiotics by impairing their efflux activity. Arylhydantoin derivatives were investigated for their potentiation of activities of selected antibiotics described as efflux substrates in Enterobacter aerogenes expressing or not AcrAB pump. Several compounds increased the bacterial susceptibility toward nalidixic acid, chloramphenicol and sparfloxacin and were further pharmacomodulated to obtain a better activity against the AcrAB producing bacteria.

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Section: Discussionmentioning

confidence: 99%

Efflux Pump Blockers in Gram-Negative Bacteria: The New Generation of Hydantoin Based-Modulators to Improve Antibiotic Activity

et al. 2016

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“…The reaffirmation of TolC as a key mechanism for export of ST1 toxins could be relevant to the management of diarrheal illness. The rapid emergence of multidrug resistance in the Enterobacteriaceae that is in part dependent on drug efflux through TolC has stimulated interest in efflux inhibitors to enhance the potency of available antimicrobial agents (53)(54)(55). Theoretically, these inhibitors could offer novel therapeutic agents for treatment of ETEC.…”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin Secretion and Delivery

et al. 2018

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Enterotoxigenic (ETEC), a heterogeneous diarrheal pathovar defined by production of heat-labile (LT) and/or heat-stable (ST) toxins, causes substantial morbidity among young children in the developing world. Studies demonstrating a major burden of ST-producing ETEC have focused interest on ST toxoids for ETEC vaccines. We examined fundamental aspects of ST biology using ETEC strain H10407, which carries and genes encoding STh and STp, respectively, in addition to genes responsible for LT. Here, we found that deletion of significantly diminished cyclic GMP (cGMP) activation in target epithelia, while deletion of had a surprisingly modest impact, and a dual mutant was not appreciably different from the mutant. However, we noted that either STh or STp recombinant peptides stimulated cGMP production and that the loss of was compensated by enhanced transcription. We also found that the TolC efflux protein was essential for toxin secretion and delivery, providing a potential avenue for efflux inhibitors in treatment of acute diarrheal illness. In addition, we demonstrated that the EtpA adhesin is required for optimal delivery of ST and that antibodies against either the adhesin or STh significantly impaired toxin delivery and cGMP activation in target T84 cells. Finally, we used FLAG epitope fusions to demonstrate that the STh propeptide sequence is secreted by ETEC, potentially providing additional epitopes for antibody neutralization. These studies collectively extend our understanding of ETEC pathogenesis and potentially inform additional avenues to mitigate disease by these common diarrheal pathogens.

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“…The reaffirmation of TolC as a key mechanism for export of ST1 toxins could be relevant to management of diarrheal illness. The rapid emergence of multi-drug resistance in the Enterobacteriaciae that is in part dependent on drug efflux through TolC has stimulated interest in efflux inhibitors to enhance the potency of available antimicrobial agents( 50–52 ). Theoretically, these inhibitors could offer novel therapeutic agents for treatment of ETEC.…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants of enterotoxigenicEscherichia coliheat-stable toxin secretion and delivery

Zhu

Luo

Davis

et al. 2018

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32Enterotoxigenic Escherichia coli (ETEC), a heterogeneous diarrheal pathovar defined by 33 production of heat-labile (LT) and/or heat-stable (ST) toxins, remain major causes of mortality 34 among children in developing regions, and cause substantial morbidity in individuals living in or 35 traveling to endemic areas. Studies demonstrating a major burden of ST-producing ETEC have 36 focused interest on ST toxoids for ETEC vaccines. We therefore examined fundamental aspects 37 of ETEC ST biology using ETEC H10407, which carries estH and estP genes encoding ST-H and 38 ST-P, respectively, in addition to eltAB genes responsible for LT. In this background, we found 39 that deletion of estH significantly diminished cGMP activation in target epithelia, while deletion 40 of estP had a surprisingly modest impact, and a dual estH/estP mutant was not appreciably 41 different than the estH mutant. Nevertheless, either ST-H or ST-P recombinant peptides 42 stimulated cGMP production. We also found that the TolC efflux protein was essential for both 43 toxin secretion and delivery, providing a potential avenue for efflux inhibitors in treatment of 44 acute diarrheal illness. In addition, we demonstrated that the EtpA adhesin is required for 45 optimal delivery of ST and that antibodies against either the adhesin or ST-H significantly 46 impaired toxin delivery and cGMP activation in target T84 cells. Finally, we used FLAG epitope 47 fusions to demonstrate that the ST-H pro-peptide sequence is secreted by the bacteria, 48 potentially providing additional targets for antibody neutralization. These studies collectively 49 extend our understanding of ETEC pathogenesis and potentially inform additional avenues to 50 mitigate disease by these common diarrheal pathogens. 51 52 475

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Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay

Cited by 36 publications

References 25 publications

Efflux Pump Blockers in Gram-Negative Bacteria: The New Generation of Hydantoin Based-Modulators to Improve Antibiotic Activity

Efflux Pump Blockers in Gram-Negative Bacteria: The New Generation of Hydantoin Based-Modulators to Improve Antibiotic Activity

Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin Secretion and Delivery

Molecular determinants of enterotoxigenicEscherichia coliheat-stable toxin secretion and delivery

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