Design, Synthesis, and Biological Evaluation of 1,3,4-Thiadiazole Derivatives as Novel Potent Peptide Deformylase Inhibitors for Combating Drug-Resistant Gram-Positive and -Negative Bacteria

Article

Author: Wang, Yaru ; Yang, Huayan ; Zhang, Ying ; Han, Ling ; Chang, Junbiao ; Zhang, Zhiqin ; Guo, Shenghai ; Yang, Shouning ; Li, Fengfeng ; Tao, Lingling ; Jiang, Yuqin ; Yang, Yujie

The prevalence of drug-resistant bacteria is a major challenge throughout the world, especially with respect to Gram-negative bacteria, such as drug-resistant Acinetobacter baumannii, which are regarded as the greatest bacterial threat to human health by the World Health Organization (WHO). In this work, 1,3,4-thiadiazole was introduced into the main skeleton of the classical peptidomimetic peptide deformylase (PDF) inhibitor in pursuit of highly efficient and broad-spectrum bacteriostatic drugs. Upon detailed structure-activity relationship study, PDF inhibitors that possess satisfactory activity against both Gram-positive and Gram-negative bacteria as well as a lower potential for methemoglobin toxicity were screened out. The mechanism of the empowered antibacterial activity against Gram-negative bacteria was also investigated. Finally, for the first time, remarkable protective efficacy against drug-resistant A. baumannii in a mouse model was achieved by a PDF inhibitor (compound 43). These findings can pave a way to new approaches to the development of novel broad-spectrum PDF inhibitors.

25 Apr 2024·Journal of Medicinal Chemistry

Toward More Selective Antibiotic Inhibitors: A Structural View of the Complexed Binding Pocket of E. coli Peptide Deformylase

Article

Author: Zouatom, Manuela ; Kirschner, Hendrik ; Zhou, Tianyi ; Hofmann, Eckhard ; Scherkenbeck, Jürgen ; Stoll, Raphael ; Heister, Nicole

Peptide deformylase (PDF) is involved in bacterial protein maturation processes. Originating from the interest in a new antibiotic, tremendous effort was put into the refinement of PDF inhibitors (PDFIs) and their selectivity. We obtained a full NMR backbone assignment the emergent additional protein backbone resonances of ecPDF 1-147 in complex with 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide (2), a potential new structural scaffold for more selective PDFIs. We also determined the complex crystal structures of E. coli PDF (ecPDF fl) and 2. Our structure suggests an alternative ligand conformation within the protein, a possible starting point for further selectivity optimization. The orientation of the second ligand conformation in the crystal structure points toward a small region of the S1' pocket, which differs between bacterial PDFs and human PDF. Moreover, we analyzed the binding mode of 2 via NMR TITAN line shape analysis, revealing an induced fit mechanism.

06 May 2016·Organic LettersQ1 · CHEMISTRY

Curtius-like Rearrangement of an Iron–Nitrenoid Complex and Application in Biomimetic Synthesis of Bisindolylmethanes

Q1 · CHEMISTRY

Article

Author: Liang, Kangjiang ; Li, Dashan ; Wu, Ting ; Xia, Chengfeng

A Curtius-like rearrangement of hydroxamates to isocyanates was discovered. This reaction was initiated from an iron(II)-nitrenoid complex, which was generated by the iron(II)-catalyzed cleavage of N-O bonds of functionalized hydroxamates. To demonstrate the efficiency of this new Curtius-like rearrangement in synthetic chemistry, a biomimetic strategy for the one-pot preparation of bisindolylmethanes was developed.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Discovery	France	Centre National de la Recherche Scientifique	15 Dec 2006

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