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TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens

The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. H...

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Detalles Bibliográficos
Autores principales: Bryan, Eric J., Sagong, Hye Yeon, Parhi, Ajit K., Grier, Mark C., Roberge, Jacques Y., LaVoie, Edmond J., Pilch, Daniel S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137614/
https://www.ncbi.nlm.nih.gov/pubmed/35625337
http://dx.doi.org/10.3390/antibiotics11050693
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author Bryan, Eric J.
Sagong, Hye Yeon
Parhi, Ajit K.
Grier, Mark C.
Roberge, Jacques Y.
LaVoie, Edmond J.
Pilch, Daniel S.
author_facet Bryan, Eric J.
Sagong, Hye Yeon
Parhi, Ajit K.
Grier, Mark C.
Roberge, Jacques Y.
LaVoie, Edmond J.
Pilch, Daniel S.
author_sort Bryan, Eric J.
collection PubMed
description The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. Here, we describe a third-generation MreB inhibitor (TXH11106) with enhanced bactericidal activity versus the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to the first- and second-generation compounds A22 and CBR-4830, respectively. Large inocula of these four pathogens are associated with a low frequency of resistance (FOR) to TXH11106. The enhanced bactericidal activity of TXH11106 relative to A22 and CBR-4830 correlates with a correspondingly enhanced capacity to inhibit E. coli MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa provide further evidence supporting MreB as the bactericidal target of the compound. Taken together, our results highlight the potential of TXH11106 as an MreB inhibitor with activity against a broad spectrum of Gram-negative bacterial pathogens of acute clinical importance.
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spelling pubmed-91376142022-05-28 TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens Bryan, Eric J. Sagong, Hye Yeon Parhi, Ajit K. Grier, Mark C. Roberge, Jacques Y. LaVoie, Edmond J. Pilch, Daniel S. Antibiotics (Basel) Article The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. Here, we describe a third-generation MreB inhibitor (TXH11106) with enhanced bactericidal activity versus the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to the first- and second-generation compounds A22 and CBR-4830, respectively. Large inocula of these four pathogens are associated with a low frequency of resistance (FOR) to TXH11106. The enhanced bactericidal activity of TXH11106 relative to A22 and CBR-4830 correlates with a correspondingly enhanced capacity to inhibit E. coli MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa provide further evidence supporting MreB as the bactericidal target of the compound. Taken together, our results highlight the potential of TXH11106 as an MreB inhibitor with activity against a broad spectrum of Gram-negative bacterial pathogens of acute clinical importance. MDPI 2022-05-20 /pmc/articles/PMC9137614/ /pubmed/35625337 http://dx.doi.org/10.3390/antibiotics11050693 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bryan, Eric J.
Sagong, Hye Yeon
Parhi, Ajit K.
Grier, Mark C.
Roberge, Jacques Y.
LaVoie, Edmond J.
Pilch, Daniel S.
TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens
title TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens
title_full TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens
title_fullStr TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens
title_full_unstemmed TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens
title_short TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens
title_sort txh11106: a third-generation mreb inhibitor with enhanced activity against a broad range of gram-negative bacterial pathogens
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137614/
https://www.ncbi.nlm.nih.gov/pubmed/35625337
http://dx.doi.org/10.3390/antibiotics11050693
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