Abstract
Elicitation through abiotic stress, including chemical elicitors like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metals on actinobacteria Streptomyces sp. SH-1312 for secondary metabolite production, with strong pharmacological activity, along with pharmacokinetics profile, was firstly investigated. The optimum metal stress conditions consisted of actinobacteria strain Streptomyces sp. SH-1312 with addition of mix metals (Co2+ + Zn2+) ions at 0.5 mM in Gause’s medium. Under these conditions, the stress metabolite anhydromevalonolactone (MVL) was produced, which was absent in the normal culture of strain and other metals combinations. Furthermore, the stress metabolite was also evaluated for its anti-oxidant and cytotoxic activities. The compound exhibited remarkable anti-oxidant activities, recording the IC50 value of 19.65 ± 5.7 µg/mL in DPPH, IC50 of 15.49 ± 4.8 against NO free radicals, the IC50 value of 19.65 ± 5.22 µg/mL against scavenging ability, and IC50 value of 19.38 ± 7.11 µg/mL for iron chelation capacity and the cytotoxic activities against PC3 cell lines were recorded with IC50 values of 35.81 ± 4.2 µg/mL after 24 h, 23.29 ± 3.8 µg/mL at 48 h, and 16.25 ± 6.5 µg/mL after 72 h. Further mechanistic studies have revealed that the compound MVL has shown its pharmacological efficacy by upregulation of P53 and BAX while downregulation of BCL-2 expression, indicating that MVL is following apoptosis in varying degrees. To better understand the pharmacological properties of MVL, in this work, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) were also evaluated. During ADMET predictions, MVL has displayed a safer profile in case of hepatotoxicity, cytochrome inhibition and also displayed as non-cardiotoxic. The compound MVL showed good binding energy in the molecular docking studies, and the results revealed that MVL bind in the active region of the target protein of P53 and BAX. This work triumphantly announced a prodigious effect of heavy metals on actinobacteria with fringe benefits as a key tool of MVL production with a strong pharmacological and pharmacokinetic profile.
Highlights
Microorganisms quickly adapt and retort to the variations in the availability and concentrations of metals within their harsh and dynamic habitat [1,2]
The impacts of elution mode, mobile phase, detection wavelength, and column temperature were conducted to determine the ideal High-performance liquid chromatography (HPLC) setting for purification of the stressed metabolite of actinobacteria
The secondary metabolite patterns of an actinobacterial strain can alter under the presence of heavy metals supplemented to the fermentation medium, as proven by two chemical and pharmacological screening approaches
Summary
Microorganisms quickly adapt and retort to the variations in the availability and concentrations of metals within their harsh and dynamic habitat [1,2]. Microorganisms that live in a stressed environment attract much attention as potential new caves of therapeutically active compounds [3,4]. Metals hamper secondary metabolite production; recent research has found that metals can stimulate or improve the action of potentially potent medically and nutraceutically relevant metabolites [1,5,6]. Thanks to the improvement of molecular biology and chemical biology techniques that imply that abiotic factors such as heavy metals may switch the production of natural compounds by modifying the attitude of secondary metabolism. The secondary metabolites produced by modern techniques like genome sequencing [7], abiotic or biotic stress [8], co-culture [9] and biosynthetic engineering proved to have enhanced pharmacological profiles compared to the compounds produced by the normal lab culture. Natural products have played an essential role in pharmacological and nutraceutical development [10,11,12]
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