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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.
Afiliação
  • Bryan EJ; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
  • Sagong HY; TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA.
  • Parhi AK; TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA.
  • Grier MC; Department of Molecular Design and Synthesis, Rutgers University Biomedical Research Innovation Cores, Piscataway, NJ 08854, USA.
  • Roberge JY; Department of Molecular Design and Synthesis, Rutgers University Biomedical Research Innovation Cores, Piscataway, NJ 08854, USA.
  • LaVoie EJ; Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, NJ 08854, USA.
  • Pilch DS; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Antibiotics (Basel) ; 11(5)2022 May 20.
Article em En | MEDLINE | ID: mdl-35625337
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article