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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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/5/693 |
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| author | Eric J. Bryan Hye Yeon Sagong Ajit K. Parhi Mark C. Grier Jacques Y. Roberge Edmond J. LaVoie Daniel S. Pilch |
| author_facet | Eric J. Bryan Hye Yeon Sagong Ajit K. Parhi Mark C. Grier Jacques Y. Roberge Edmond J. LaVoie Daniel S. Pilch |
| author_sort | Eric J. Bryan |
| collection | DOAJ |
| 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 <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, and <i>Pseudomonas aeruginosa</i> 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 <i>E. coli</i> MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in <i>E. coli</i>, <i>K. pneumoniae</i>, <i>A. baumannii</i>, and <i>P. aeruginosa</i> 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. |
| first_indexed | 2024-03-10T03:27:53Z |
| format | Article |
| id | doaj.art-f8ac5228aca5430cb41dd1a89b48c18b |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T03:27:53Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-f8ac5228aca5430cb41dd1a89b48c18b2023-11-23T09:49:47ZengMDPI AGAntibiotics2079-63822022-05-0111569310.3390/antibiotics11050693TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial PathogensEric J. Bryan0Hye Yeon Sagong1Ajit K. Parhi2Mark C. Grier3Jacques Y. Roberge4Edmond J. LaVoie5Daniel S. Pilch6Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USATAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USATAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USADepartment of Molecular Design and Synthesis, Rutgers University Biomedical Research Innovation Cores, Piscataway, NJ 08854, USADepartment of Molecular Design and Synthesis, Rutgers University Biomedical Research Innovation Cores, Piscataway, NJ 08854, USADepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers—The State University of New Jersey, Piscataway, NJ 08854, USADepartment of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USAThe 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 <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, and <i>Pseudomonas aeruginosa</i> 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 <i>E. coli</i> MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in <i>E. coli</i>, <i>K. pneumoniae</i>, <i>A. baumannii</i>, and <i>P. aeruginosa</i> 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.https://www.mdpi.com/2079-6382/11/5/693bactericidal efficacy<i>Escherichia coli</i><i>Klebsiella pneumoniae</i><i>Acinetobacter baumannii</i><i>Pseudomonas aeruginosa</i>noncompetitive inhibition of MreB ATPase activity |
| spellingShingle | Eric J. Bryan Hye Yeon Sagong Ajit K. Parhi Mark C. Grier Jacques Y. Roberge Edmond J. LaVoie Daniel S. Pilch TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens Antibiotics bactericidal efficacy <i>Escherichia coli</i> <i>Klebsiella pneumoniae</i> <i>Acinetobacter baumannii</i> <i>Pseudomonas aeruginosa</i> noncompetitive inhibition of MreB ATPase activity |
| 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 | bactericidal efficacy <i>Escherichia coli</i> <i>Klebsiella pneumoniae</i> <i>Acinetobacter baumannii</i> <i>Pseudomonas aeruginosa</i> noncompetitive inhibition of MreB ATPase activity |
| url | https://www.mdpi.com/2079-6382/11/5/693 |
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