Solid-Phase Synthesis and Antibacterial Activity of Cyclohexapeptide Wollamide B Analogs

• Published in: ACS combinatorial science Vol. 20; no. 3; pp. 172 - 185
• Main Authors: Tsutsumi, Lissa S, Elmore, John M, Dang, Uyen T, Wallace, Miranda J, Marreddy, Ravikanthreddy, Lee, Robin B, Tan, Ghee T, Hurdle, Julian G, Lee, Richard E, Sun, Dianqing
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.03.2018; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Chemistry; Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary; Combinatorial Chemistry Techniques; Gram-Positive Bacteria - drug effects; Humans; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis - drug effects; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Solid-Phase Synthesis Techniques - methods; Structure-Activity Relationship; desotamide; solid-phase peptide synthesis; structure−activity relationships; antibacterial; antituberculosis; cyclic hexapeptides; wollamide; CLOSTRIDIUM-DIFFICILE INFECTION; ANTIBIOTICS; TUBERCULOSIS; MEMBRANE; STEREOCHEMISTRY; GRAM-POSITIVE BACTERIA; structure-activity relationships; STREPTOMYCES; UREA LIBRARY; EXTENSIVELY DRUG-RESISTANT
• ISSN: 2156-8952; 2156-8944
• DOI: 10.1021/acscombsci.7b00189

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.