RESUMEN
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.
Asunto(s)
Aciltransferasas/metabolismo , Antiinfecciosos/química , Proteínas Bacterianas/metabolismo , Resorcinoles/química , Aciltransferasas/antagonistas & inhibidores , Aciltransferasas/clasificación , Aciltransferasas/genética , Antiinfecciosos/aislamiento & purificación , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/clasificación , Proteínas Bacterianas/genética , COVID-19/patología , COVID-19/virología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Filogenia , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Resorcinoles/aislamiento & purificación , Resorcinoles/metabolismo , Resorcinoles/farmacología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Streptomyces/enzimología , Espectrometría de Masas en TándemRESUMEN
A new (1, grincamycin L) and two known (2 and 3) angucycline derivatives were obtained from the fermentation of deepsea-derived Streptomyces lusitanus OUCT16-27 strain. The structures of 1-3 were elucidated based on the LC-MS analysis together with 1D and 2D NMR data assignment. In the antibacterial assay, 1 and 2 exhibited moderate growth inhibitions against multi-drug resistant (MDR) strains of E. faecium, E. faecalis and S. aureus with the minimum inhibitory concentrations (MICs) of 3.12-6.25 µg/mL.