New insights into the neuroprotective and beta-secretase1 inhibitor profiles of tirandamycin B isolated from a newly found Streptomyces composti sp. nov.

Abstract

Tirandamycin (TAM B) is a tetramic acid antibiotic discovered to be active on a screen designed to find compounds with neuroprotective activity. The producing strain SBST2-5T is an actinobacterium that was isolated from wastewater treatment bio杝ludge compost collected from Suphanburi province Thailand. Taxonomic characterization based on a polyphasic approach indicates that strain SBST2-5T is a member of the genus Streptomyces and shows low average nucleotide identity (ANI) (81.7%) average amino-acid identity (AAI) (78.5%) and digital DNA-DNA hybridization (dDDH) (25.9%) values to its closest relative Streptomyces thermoviolaceus NBRC 13905T values that are significantly below the suggested cut-off values for the species delineation indicating that strain SBST2-5T could be considered to represent a novel species of the genus Streptomyces. The analysis of secondary metabolites biosynthetic gene clusters (smBGCs) in its genome and chemical investigation led to the isolation of TAM B. Interestingly TAM B at 20�g/mL displayed a suppressive effect on beta-secretase 1 (BACE1) with 68.69 ? 8.84% inhibition. Molecular docking simulation reveals the interaction mechanism between TAM B and BACE1 that TAM B was buried in the pocket of BACE-1 by interacting with amino acids Thr231 Asp 228 Gln73 Lys 107 via hydrogen bond and Leu30 Tyr71 Phe108 Ile118 via hydrophobic interaction indicating that TAM B represents a potential active BACE1 inhibitor. Moreover TAM B can protect the neuron cells significantly (% neuron viability = 83.10 ? 9.83% and 112.72 ? 6.83%) from oxidative stress induced by serum deprivation and A?1� administration models at 1爊g/mL respectively without neurotoxicity on murine P19-derived neuron cells nor cytotoxicity against Vero cells. This study was reportedly the first study to show the neuroprotective and BACE1 inhibitory activities of TAM B. ? 2023 The Author(s).