Abstract
Literature surveys, taxonomical differences, and bioassay results have been utilized in the discovery of new natural products to aid in Actinomycetes isolate-selection. However, no or less investigation have been done on establishing the differences in metabolomic profiles of the isolated microorganisms. The study aims to utilise bioassay- and metabolomics-guided tools that included dereplication study and multivariate analysis of the NMR and mass spectral data of microbial extracts to assist the selection of isolates for scaling-up the production of antimicrobial natural products. A total of 58 actinomycetes were isolated from different soil samples collected from Ihnasia City, Egypt and screened for their antimicrobial activities against indicator strains that included Bacillus subtilis, Escherichia coli, methicillin-resistant Staphylococcus aureus and Candida albicans. A number of 25 isolates were found to be active against B. subtilis and/or to at least one of the tested indicator strains. Principal component analyses showed chemical uniqueness for four outlying bioactive actinomycetes extracts. In addition, Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) and dereplication study led us to further select two outlying anti-MRSA active isolates MS.REE.13 and 22 for scale-up work. MS.REE.13 and 22 exhibited zones of inhibition at 19 and 13 mm against MRSA, respectively. A metabolomics-guided approach provided the steer to target the bioactive metabolites (P<0.01) present in a crude extract or fraction even at nanogram levels but it was a challenge that such low-yielding bioactive natural products would be feasible to isolate. Validated to occur only on the active side of OPLS-DA loadings plot, the isolated compounds exhibited medium to weak antibiotic activity with MIC values between 250 and 800 μM. Two new compounds, P_24306 (C10H13N2) and N_12799 (C18H32O3) with MICs of 795 and 432 μM, were afforded from the scale-up of MS.REE. 13 and 22, respectively.
Highlights
Natural products research has played a vital role in drug discovery and development during the last decades [1]
Egyptian soils have not been vastly investigated for their actinobacterial reservoir and only few reports have been published on actinobacteria isolated from this ecosystem [9,10,11]
As mentioned in a previous report, polysaccharides like starch as carbon source present in International Streptomyces Project 4 (ISP4) is commonly used for optimum production of antibiotics due to supporting slower microbial, growth which is suitable for antibiotics biosynthesis [59]
Summary
Natural products research has played a vital role in drug discovery and development during the last decades [1]. About 45% of the 22,000 reported microbial natural products are produced by actinomycetes, 38% are fungal metabolites and only 17% are from unicellular bacteria [3, 4]. Species of the genus Streptomyces have been described to produce about 75% of the reported metabolites from actinomycetes [6, 7]. These secondary metabolites are mainly biosynthesized by either polyketide or non-ribosomal peptide synthetases [8]. Egyptian soils have not been vastly investigated for their actinobacterial reservoir and only few reports have been published on actinobacteria isolated from this ecosystem [9,10,11]
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