In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 3 ( 2023-3-31), p. e0283674-
Abstract:
The overconsumption and inappropriate use of antibiotics is escalating antibiotic resistance development, which is now one of the 10 top threats to global health. Introducing antibiotics with a novel mode of action into clinical use is urgently needed to address this issue. Deliberately inducing aggregation of target proteins and disrupting protein homeostasis in bacteria via amyloidogenic peptides, also called Pept-ins (from pept ide in terferors), can be lethal to bacteria and shows considerable promise as a novel antibiotic strategy. However, the translation of Pept-ins into the clinic requires further investigation into their mechanism of action and improvement of their therapeutic window. Therefore, we performed systematic structure modifications of 2 previously discovered Pept-ins, resulting in 179 derivatives, and investigated the corresponding impact on antimicrobial potency, cellular accumulation, and ability to induce protein aggregation in bacteria, in vitro aggregation property, and toxicity on mammalian cells. Our results show that both Pept-in accumulation and aggregation of target proteins in bacteria are requisite for Pept-in mediated antimicrobial activity. Improvement of these two parameters can be achieved via increasing the number of arginine residues, increasing Pept-in aggregation propensity, optimizing the aggregate core structure, adopting β-turn linkers, or forming a disulphide bond. Correspondingly, improvement of these two parameters can enhance Pept-in antimicrobial efficacy against wildtype E . coli BL21 used in the laboratory as well as clinically isolated multidrug-resistant strain E . coli ATCC, A . baumannii , and K . pneumoniae .
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0283674
DOI:
10.1371/journal.pone.0283674.g001
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10.1371/journal.pone.0283674.g002
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10.1371/journal.pone.0283674.g003
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10.1371/journal.pone.0283674.g004
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10.1371/journal.pone.0283674.g005
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10.1371/journal.pone.0283674.g006
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10.1371/journal.pone.0283674.t001
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10.1371/journal.pone.0283674.t002
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10.1371/journal.pone.0283674.s001
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10.1371/journal.pone.0283674.s002
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10.1371/journal.pone.0283674.s003
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10.1371/journal.pone.0283674.s004
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10.1371/journal.pone.0283674.s005
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10.1371/journal.pone.0283674.s006
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10.1371/journal.pone.0283674.s007
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10.1371/journal.pone.0283674.s008
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10.1371/journal.pone.0283674.s009
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10.1371/journal.pone.0283674.s010
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10.1371/journal.pone.0283674.s011
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10.1371/journal.pone.0283674.s012
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10.1371/journal.pone.0283674.s013
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10.1371/journal.pone.0283674.s014
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10.1371/journal.pone.0283674.s015
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10.1371/journal.pone.0283674.s016
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10.1371/journal.pone.0283674.s017
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10.1371/journal.pone.0283674.s018
DOI:
10.1371/journal.pone.0283674.s019
DOI:
10.1371/journal.pone.0283674.s020
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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