Solid-Phase Synthesis and Antibacterial Activity of Cyclohexapeptide Wollamide B Analogs
Autor: | Julian G Hurdle, Ghee Teng Tan, Robin B. Lee, Lissa S. Tsutsumi, Miranda J. Wallace, John M Elmore, Ravikanthreddy Marreddy, Richard E. Lee, Dianqing Sun, Uyen T. Dang |
---|---|
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
medicine.drug_class Stereochemistry Gram-positive bacteria 030106 microbiology Antitubercular Agents Microbial Sensitivity Tests Antimycobacterial Gram-Positive Bacteria 01 natural sciences Peptides Cyclic Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Solid-phase synthesis Amide medicine Structure–activity relationship Combinatorial Chemistry Techniques Humans Solid-Phase Synthesis Techniques Natural product biology Molecular Structure 010405 organic chemistry General Chemistry General Medicine Mycobacterium tuberculosis biology.organism_classification 0104 chemical sciences Anti-Bacterial Agents chemistry Antibacterial activity Bacteria |
Zdroj: | ACS combinatorial science. 20(3) |
ISSN: | 2156-8944 |
Popis: | Herein we report the antibacterial structure-activity relationships of cyclic hexapeptide wollamide analogs derived from solid-phase library synthesis. Wollamide B, a cyclic hexapeptide natural product, has been previously found to have activity against Mycobacterium bovis. To further evaluate its antimycobacterial/antibacterial potential, 27 peptides including wollamides A/B, and desotamide B, were synthesized and subsequently tested against a panel of clinically significant bacterial pathogens. Biological evaluation revealed that the cyclic scaffold, amide functionality in position I, tryptophan residue in position V, and the original stereochemistry pattern of the core scaffold were key for antituberculosis and/or antibacterial activity. In addition, against M. tuberculosis and Gram-positive bacteria, residues in position II and/or VI greatly impacted antibacterial activity and selectivity. Wollamides A (3) and B (2) along with their corresponding II (l-Leu) analog 10 retained the most promising antituberculosis activity, with the lowest minimum inhibitory concentration (MIC) against virulent M. tuberculosis H37Rv (MIC = 1.56 μg/mL), as well as desirable selectivity indices (100). Importantly, the antimicrobial activities of wollamides A and B do not result from disruption of the bacterial membrane, warranting further investigation into their mechanism of action. |
Databáze: | OpenAIRE |
Externí odkaz: |