Discovery of anti-infective adipostatins through bioactivity-guided isolation and heterologous expression of a type III polyketide synthase

• Published in: Bioorganic chemistry 2021-07, Vol.112, p.104925-104925, Article 104925
• Main Authors: Hou, Lukuan, Li, Ying, Wu, Qihao, Li, Miyang, Older, Ethan A., Tang, Xiaoyu, Nagarkatti, Prakash, Nagarkatti, Mitzi, Liu, Yuan, Li, Lingjun, Fan, Daping, Bugni, Tim S., Shang, Zhuo, Li, Jie
• Format: Article
• Language: English
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - classification; Acyltransferases - genetics; Acyltransferases - metabolism; Anti-Infective Agents - chemistry; Anti-Infective Agents - isolation & purification; Anti-Infective Agents - metabolism; Anti-Infective Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - classification; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - metabolism; COVID-19 - pathology; COVID-19 - virology; Drug Evaluation, Preclinical; ESKAPE pathogens inhibition; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Heterologous expression; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Conformation; New adipostatins; Phylogeny; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Resorcinols - chemistry; Resorcinols - isolation & purification; Resorcinols - metabolism; Resorcinols - pharmacology; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; SARS-CoV-2 main protease inhibition; Streptomyces - enzymology; Tandem Mass Spectrometry; Type III polyketide synthase
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104925

[Display omitted] •Adipostatins against SARS-CoV-2 main protease and drug-resistant pathogens.•Heterologous expression of the polyketide synthase generated new adipostatins.•Diversifying the structures and enhancing the bioactivities of adipostatins. Antibiotic resistance and emerging viral pandemics have posed an urgent need for new anti-infective drugs. By screening our microbial extract library against the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the notorious ESKAPE pathogens, an active fraction was identified and purified, leading to an initial isolation of adipostatins A (1) and B (2). In order to diversify the chemical structures of adipostatins toward enhanced biological activities, a type III polyketide synthase was identified from the native producer, Streptomyces davawensis DSM101723, and was subsequently expressed in an E. coli host, resulting in the isolation of nine additional adipostatins 3–11, including two new analogs (9 and 11). The structures of 1–11 were established by HRMS, NMR, and chemical derivatization, including using a microgram-scale meta-chloroperoxybenzoic acid epoxidation-MS/MS analysis to unambiguously determine the double bond position in the alkyl chain. The present study discovered SARS-CoV-2 main protease inhibitory activity for the class of adipostatins for the first time. Several of the adipostatins isolated also exhibited antimicrobial activity against selected ESKAPE pathogens.