Abstract
Polymyxin E belongs to cationic polypeptide antibiotic bearing four types of direct precursor amino acids including L-2,4-diaminobutyric acid (L-Dab), L-Leu, D-Leu, and L-Thr. The objective of this study is to evaluate the effect of addition of precursor amino acids during fermentation on polymyxin E biosynthesis in Paenibacillus polymyxa. The results showed that, after 35 h fermentation, addition of direct precursor amino acids to certain concentration significantly inhibited polymyxin E production and affected the expression of genes involved in its biosynthesis. L-Dab repressed the expression of polymyxin synthetase genes pmxA and pmxE, as well as 2,4-diaminobutyrate aminotransferase gene ectB; both L-Leu and D-Leu repressed the pmxA expression. In addition, L-Thr affected the expression of not only pmxA, but also regulatory genes spo0A and abrB. As L-Dab precursor, L-Asp repressed the expression of ectB, pmxA, and pmxE. Moreover, it affected the expression of spo0A and abrB. In contrast, L-Phe, a nonprecursor amino acid, had no obvious effect on polymyxin E biosynthesis and those biosynthesis-related genes expression. Taken together, our data demonstrated that addition of precursor amino acids during fermentation will inhibit polymyxin E production probably by affecting the expression of its biosynthesis-related genes.
Highlights
Polymyxin E is biosynthesized in Paenibacillus polymyxa [1]
We found that addition of precursor amino acids will suppress polymyxin E production probably by affecting the expression of polymyxin E biosynthesisrelated genes
In the following experiments, a fermentation period from 35 h to 72 h was selected for monitoring polymyxin E production and the expression of genes involved in polymyxin E biosynthesis
Summary
Polymyxin E is biosynthesized in Paenibacillus polymyxa [1]. It has been used as an important therapy for infection caused by Gram-negative pathogens since 1959. Multidrug resistance in pathogens to almost all currently available antibiotics is becoming a big threat for human health, leaving very limited choices for clinical therapy [3,4,5]. The basic structure of polymyxin E is a cyclic heptapeptide with a tripeptide side chain acylated by a fatty acid at the amino terminus [8, 9]. It is biosynthesized by a multienzyme nonribosomal peptide synthetase system (NRPS) [1, 10,11,12]. A gene cluster for its biosynthesis has been determined to have five open reading frames, pmxA, pmxB, pmxE, pmxC, and pmxD, encoding three polymyxin synthetases
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