Enhancement of avermectin and ivermectin production by overexpression of the maltose ATP-binding cassette transporter in Streptomyces avermitilis

State Key Laboratories for Agrobiotechnology and College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Bioresource Technology (Impact Factor: 4.49). 12/2010; 101(23):9228-35. DOI: 10.1016/j.biortech.2010.06.132
Source: PubMed


We investigated the function of maltose ABC transporter system encoded by malEFG-a and the effect of its overexpression on antibiotic production in Streptomyces avermitilis. A malEFG-a deletion mutant was unable to grow in a minimal medium with maltose as sole carbon source and produce avermectin. Maltose utilization and avermectin production were restored by introduction of a single copy of malEFG-a. RT-PCR analysis showed that the expression of malE-a was induced by maltose, and was strongly repressed by glucose. When multi-copy, integrative malEFG-a gene expression vectors were introduced into wild-type strain ATCC31267 and ivermectin-producer OI-31, antibiotic production increased by 2.6- to 3.3-fold and the time required for fermentation decreased by about 10%. The overexpression of malEFG-a improved the utilization rate of starch, and thereby enhanced avermectin production. Such an approach would be useful for the improvement of commercial antibiotic production using starch as the main carbon source in the fermentation process.

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    • "respectively, in a shorter duration of fermentation time. Thereby, overexpression of these genes could efficiently utilize starch as a sole carbon source, while ultimately increasing the production of AVM derivatives (Li et al. 2010b). Protein alignment analysis revealed the predicted function of the gene avtAB as an ABC transporter. "
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    ABSTRACT: Avermectins (AVMs), produced by Streptomyces avermitilis MA-4680 (or ATCC 31267, NRRL 8165, NCBIM 12804), are 16-member macrocylic lactones that play very important functions as bactericidal and antiparasitic agents against nematodes and anthropods, as well as Mycobacterium tuberculosis H37Rv. Since its discovery in 1975, use of AVM has been widely spreading around the globe. To date, the whole genome sequence of S. avermitilis K139 has been acquired, in which the AVM biosynthetic gene cluster was the most highly investigated to mine the genes responsible for functional as well as regulatory roles. Therefore, significant progress has been achieved for understanding and manipulating the biosynthesis, improved production, regulation mechanism, side effects, as well as the resistance of AVMs and their derivatives. These findings will facilitate further strain improvement and biosynthesis of novel derivatives bearing stable and improved biological activities, as well as overcoming the resistance mechanism to open up a bright period for these compounds. In this review, we have summarized and analyzed the update in advanced progress in biochemistry and biotechnological approaches used for the production of AVMs and their derivatives.
    Applied Microbiology and Biotechnology 08/2014; DOI:10.1007/s00253-014-5926-x · 3.34 Impact Factor
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    • "S. avermitilis has 428 putative ORFs related to ABC transporters, but the transported substrates are mostly unknown. The overexpression of maltose importer-type ABC transporter could enhance the production of avermectin and ivermectin (Li et al. 2010), but few studies have reported on exporters in S. avermitilis, and little is known about drug efflux pumps for avermectins. Upstream of the avermectin biosynthetic gene cluster is the avtAB operon (sav933–934) which encodes a putative ABC multidrug efflux transporter (Fig. 1b). "
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    ABSTRACT: Avermectins are 16-membered macrocyclic polyketides with potent antiparasitic activities, produced by Streptomyces avermitilis. Upstream of the avermectin biosynthetic gene cluster, there is the avtAB operon encoding the ABC transporter AvtAB, which is highly homologous to the mammalian multidrug efflux pump P-glycoprotein (Pgp). Inactivation of avtAB had no effect, but increasing the concentration of avtAB mRNA 30-500-fold, using a multi-copy plasmid in S. avermitilis, enhanced avermectin production about two-fold both in the wild-type and in a high-yield producer strain on agar plates. In liquid industrial fermentation medium, the overall productivity of avermectin B1a in the engineered high-yield producer was improved for about 50%, from 3.3 to 4.8 g/l. In liquid YMG medium, moreover, the ratio of intracellular to extracellular accumulation of avermectin B1a was dropped from 6:1 to 4.5:1 in response to multiple copies of avtAB. Additionally, the overexpression of avtAB did not cause any increased expression of the avermectin biosynthetic genes through RT-PCR analysis. We propose that the AvtAB transporter exports avermectin, and thus reduces the feedback inhibition on avermectin production inside the cell. This strategy may be useful for enhancing the production of other antibiotics.
    Applied Microbiology and Biotechnology 06/2011; 92(2):337-45. DOI:10.1007/s00253-011-3439-4 · 3.34 Impact Factor
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    Biotechnology and Bioprocess Engineering 10/2012; 17(5). DOI:10.1007/s12257-012-0173-4 · 1.11 Impact Factor
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