22174-00-1Relevant academic research and scientific papers
Rational design of a new class of toll-like receptor 4 (tlr4) tryptamine related agonists by means of the structure- and ligand-based virtual screening for vaccine adjuvant discovery
Honegr, Jan,Dolezal, Rafael,Malinak, David,Benkova, Marketa,Soukup, Ondrej,De Almeida, Joyce S. F. D.,Franca, Tanos C. C.,Kuca, Kamil,Prymula, Roman
, (2018)
In order to identify novel lead structures for human toll-like receptor 4 (hTLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the hTLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate hTLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.
ADJUVANT-ANTIBIOTIC COMBINATION AGAINST GRAM-NEGATIVE BACTERIA
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Paragraph 0091; 0094; 0096, (2021/10/22)
Tryptamine ureas and derivatives function as adjuvants to sensitize gram-negative bacteria to the effects of polymyxin antibiotics (e.g., colistin). Combination therapy of polymyxin antibiotics and the adjuvants has utility in the treatment of gram-negati
Second-Generation Tryptamine Derivatives Potently Sensitize Colistin Resistant Bacteria to Colistin
Minrovic, Bradley M.,Hubble, Veronica B.,Barker, William T.,Jania, Leigh A.,Melander, Roberta J.,Koller, Beverly H.,Melander, Christian
supporting information, p. 828 - 833 (2019/05/08)
Antibiotic resistance has significantly increased since the beginning of the 21st century. Currently, the polymyxin colistin is typically viewed as the antibiotic of last resort for the treatment of multidrug resistant Gram-negative bacterial infections. However, increased colistin usage has resulted in colistin-resistant bacterial isolates becoming more common. The recent dissemination of plasmid-borne colistin resistance genes (mcr 1-8) into the human pathogen pool is further threatening to render colistin therapy ineffective. New methods to combat antibiotic resistant pathogens are needed. Herein, the utilization of a colistin-adjuvant combination that is effective against colistin-resistant bacteria is described. At 5 μM, the lead adjuvant, which is nontoxic to the bacteria alone, increases colistin efficacy 32-fold against bacteria containing the mcr-1 gene and effects a 1024-fold increase in colistin efficacy against bacteria harboring chromosomally encoded colistin resistance determinants; these combinations lower the colistin minimum inhibitory concentration (MIC) to or below clinical breakpoint levels (≤2 μg/mL).
