The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>

ABSTRACT Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the...

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Autores principales: Wooseong Kim, Guijin Zou, Wen Pan, Nico Fricke, Hammad A. Faizi, Soo Min Kim, Rajamohammed Khader, Silei Li, Kiho Lee, Iliana Escorba, Petia M. Vlahovska, Huajian Gao, Frederick M. Ausubel, Eleftherios Mylonakis
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:4c6e5367321845828598c4354294512c2021-11-15T15:56:46ZThe Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>10.1128/mBio.01140-202150-7511https://doaj.org/article/4c6e5367321845828598c4354294512c2020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01140-20https://doaj.org/toc/2150-7511ABSTRACT Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.Wooseong KimGuijin ZouWen PanNico FrickeHammad A. FaiziSoo Min KimRajamohammed KhaderSilei LiKiho LeeIliana EscorbaPetia M. VlahovskaHuajian GaoFrederick M. AusubelEleftherios MylonakisAmerican Society for Microbiologyarticlepersistersantibiotic toleranceantimicrobial resistanceMRSAmembrane-active antimicrobialsantibioticMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution DOAJ
collection DOAJ
language EN
topic persisters
antibiotic tolerance
antimicrobial resistance
MRSA
membrane-active antimicrobials
antibiotic
Microbiology
QR1-502
spellingShingle persisters
antibiotic tolerance
antimicrobial resistance
MRSA
membrane-active antimicrobials
antibiotic
Microbiology
QR1-502
Wooseong Kim
Guijin Zou
Wen Pan
Nico Fricke
Hammad A. Faizi
Soo Min Kim
Rajamohammed Khader
Silei Li
Kiho Lee
Iliana Escorba
Petia M. Vlahovska
Huajian Gao
Frederick M. Ausubel
Eleftherios Mylonakis
The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
description ABSTRACT Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.
format article
author Wooseong Kim
Guijin Zou
Wen Pan
Nico Fricke
Hammad A. Faizi
Soo Min Kim
Rajamohammed Khader
Silei Li
Kiho Lee
Iliana Escorba
Petia M. Vlahovska
Huajian Gao
Frederick M. Ausubel
Eleftherios Mylonakis
author_facet Wooseong Kim
Guijin Zou
Wen Pan
Nico Fricke
Hammad A. Faizi
Soo Min Kim
Rajamohammed Khader
Silei Li
Kiho Lee
Iliana Escorba
Petia M. Vlahovska
Huajian Gao
Frederick M. Ausubel
Eleftherios Mylonakis
author_sort Wooseong Kim
title The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_short The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_fullStr The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full_unstemmed The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_sort neutrally charged diarylurea compound pq401 kills antibiotic-resistant and antibiotic-tolerant <named-content content-type="genus-species">staphylococcus aureus</named-content>
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/4c6e5367321845828598c4354294512c
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