Heterologous production of ribostamycin derivatives in engineered Escherichia coli.
Aminoglycosides are a class of important antibiotic compounds used for various therapeutic indications. In recent times, their efficacy has been curtailed due to the rapid development of bacterial resistance. There is a need to develop novel derivatives with an improved spectrum of activity and higher sensitivity against pathogenic bacteria. Although efforts have been focused on the development of newer therapeutic agents by chemical synthesis, to our knowledge, there has been no attempt to harness the potential of microorganisms for this purpose. Escherichia coli affords a widely studied cellular system that could be utilized not only for understanding but also for attempting to engineer the biosynthetic pathway of secondary metabolites. The primary metabolic pathway of E. coli can be engineered to divert the precursor pool required for the biosynthesis of secondary metabolites. Utilizing this approach previously, we engineered E. coli host and generated E. coli M1. Here, we produced a ribostamycin derivative in the engineered host by heterologous expression of the recombinants constructed from the genes encoding the biosynthetic pathway in aminoglycoside-producing strains. The products obtained from the transformants were isolated, analyzed and verified to be ribostamycin derivatives. The study further demonstrated the importance of E. coli as surrogate antibiotic producer and also offered future possibility for the production of other aminoglycoside derivatives through genetic engineering and expression in a heterologous background.
Kurumbang
Nagendra Prasad
NP
Institute of Biomolecule Reconstruction, Department of Pharmaceutical Engineering, Sun Moon University, 100, Kalsan-ri, Tangjeonmyun, Asansi, Chungnam 336-708, Republic of Korea.
Park
Je Won
JW
Yoon
Yeo Joon
YJ
Liou
Kwangkyoung
K
Sohng
Jae Kyung
JK
D000595:Amino Acid Sequence; D000617:Aminoglycosides / Q000096:biosynthesis; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000378:metabolism; D053898:Biosynthetic Pathways; D003001:Cloning, Molecular; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005798:Genes, Bacterial; D005818:Genetic Engineering; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012271:Ribostamycin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D014169:Transformation, Bacterial
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D011994:Recombinant Proteins; D012271:Ribostamycin; D010088:Oxidoreductases