Abstract
Antibiotics play an important role in human health. Most antibiotics are derived from microbial secondary metabolites. Amphotericin is a polyene macrolide antibiotic synthesized by Streptomyces nodosus. S. nodosus ZJB2016050 with high-yield amphotericin B (AmB) was obtained by traditional mutagenesis using S. nodosus ATCC14899 as the original strain. The differences in the characterization of the two strains were found in color, mycelium morphology, and AmB yield. Subsequent comparative transcriptome explained the yield differences between the two strains. Pathways including the carbohydrate metabolic pathway and the secondary product synthesis pathway were targeted. The upregulation of glucokinase, phosphoglycerate mutase, and pyruvate dehydrogenase accelerates the consumption of glucose and has great effects on the accumulation of precursors. One of the competitive secondary metabolites of the polyketone synthetase (PKS) II type sapromomycin analog synthesis gene cluster was downregulated, which competes for malonyl-CoA. Five PKS modules (except for the first module amphA) of the amphotericin synthetic gene cluster in the high-yielding strain were downregulated, which resulted in the total amphotericin A (AmA) and AmB of S. nodosus ZJB2016050 being less than that of the wild-type S. nodosus ATCC14899. Combined with gene differential expression in the pentose phosphate pathway and the reaction mechanism of the ER5 domain, the reason that S. nodosus ZJB2016050 preferred to synthesize AmB was probably related to intracellular reduction.
Highlights
Fungal infection is a major global problem with 1.6 million people dead per year (McAlister and Shapiro, 2019)
The bulge in colony morphology means that the mutant strains of the latter two types have little effect on the growth rate, which is similar to the original strain S. nodosus ATCC14899, while the difference in the spore color is likely related to the intracellular pigment, which is likely related to the mass of the spores
A mutated high-yield strain S. nodosus ZJB2016050 was obtained in our lab and had greater advantages in industrial production
Summary
Fungal infection is a major global problem with 1.6 million people dead per year (McAlister and Shapiro, 2019). The most effective way to target fungal infections is to use antibiotics. The current situation is not optimistic with the increasing antibiotics resistance of pathogenic microorganisms and the lack of novel antibiotic discovery (Amara et al, 2018). Amphotericin B is produced by Streptomyces nodosus, which belongs to polyene macrolide antibiotic and is widely used in clinical treatment with good effect (AbuSalah, 1996; Hartsel and Bolard, 1996). AmB is effective against emerging pathogens such as Candida auris, a kind of yeast that is multidrug-resistant, is highly infectious, and has high mortality (Escandón et al, 2019; Forsberg et al, 2019). A new treatment method of AmB in the clinic, such as short-course high-dose treatment, was developed to improve the curative effect (Jarvis et al, 2019)
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