Shayan Ahmed, Jamia Millia Islamia, New Delhi
Biosynthetic Gene Clusters in Streptomyces:
Streptomyces genomes have a huge reservoir of uncharacterized Biosynthetic Gene Clusters (BGCs) producing drug-like compounds, sparking renewed interest in these species. However, in laboratory circumstances, a substantial percentage of these BGCs fail to generate measurable amounts of the anticipated chemicals. As a result, cryptic or silent metabolism is a substantial impediment to genomics-driven medication development.
Synthetic biology, cell signalling, and stress processes are often utilized to activate silent BGCs for chemical discovery since they are considered to be transcriptionally inadequate. To narrow the drug discovery gap, Cryptic metabolism in Streptomyces is still required to unlock the full biosynthetic potential of these organisms. Cryptic metabolism is a well-known issue in the field, with inadequate BGC transcription being cited as the primary cause of biosynthetic silence. This assumption is being challenged by a growing body of evidence that shows that not all cryptic clusters are transcriptionally silent.
Unlocking Cryptic Metabolism in Streptomyces:
Researchers have employed a comparative metabologenomic strategy to figure out why some Streptomyces strains produce antibiotics readily while others have BGCs that appear to be silent. This study focused on Polycyclic Tetramate Macrolactam (PTM) antibiotics because these provide an ideal model system for multi-strain comparative studies. PTM BGCs can have as few as three genes, making regulatory studies much easier.
The relative ubiquity of PTM BGCs is another benefit. The Streptomyces griseus clade was chosen as a particularly useful cohort for these comparisons since many strains within it have developed active or cryptic PTM BGCs. This research began with a comparison of the genomes and PTM production patterns of a group of PTM locus-bearing S. griseus clade strains, which comprised both robust and weak PTM producers. In comparison to the remainder of the test strains, this resulted in the discovery of a subclade with consistently greater PTM production and PTM BGC promoter strengths.
Results & Outcomes of the Study:
By correlating the genomes and PTM production patterns of various strains, researchers comprehensively mapped the architecture of the PTM promoter within the group. The majority of promoter characteristics were found to be preserved across the group. Through gene deletion, binding site modification, and in vitro binding studies, the well-known global regulator AdpA was demonstrated to perform a direct positive function in PTM locus control. All members of the examined clade have AdpA binding sites in their PTM promoters.
This demonstrated that these promoters are activated directly by the global regulator AdpA, and that tiny promoter insertion-deletion lesions (indels) distinguish weaker from stronger PTM producers. In addition, the researchers identified an unexpected link between strong PTM expression and coproduction of griseorhodin pigment, whereas with weaker S. griseus–clade PTM producers were unable to generate the latter.
Significance of the Study:
This research focuses on promoter indels and biosynthetic interactions as significant genetically encoded variables that influence BGC outputs, offering mechanistic insights that will likely apply to additional Streptomyces BGCs. The revelation of PTM dependency on griseorhodin was unexpected, and it serves as a rare and cautionary example of how genome reduction might have unforeseen repercussions for larger strain-wide BGC function. This study emphasizes comparative metabologenomics as a valuable tool for exposing genetic characteristics that distinguish strong antibiotic manufacturers from weaker ones. As a result, such knowledge is extremely useful for streamlining focused discovery efforts and directing novel rational engineering techniques to activate specific silent BGCs.
Also read: Ribovore: An rRNA sequence validation system for GenBank submissions
Reference:
- Qi, Y., Nepal, K. K., & Blodgett, J. (2021). A comparative metabologenomic approach reveals mechanistic insights into Streptomyces antibiotic crypticity. Proceedings of the National Academy of Sciences of the United States of America, 118(31), e2103515118. https://doi.org/10.1073/pnas.2103515118
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Author info:
Shayan Ahmed is currently pursuing a Master of Science degree in Microbiology from the Department of Biosciences, Jamia Millia Islamia, New Delhi. His area of research interest lies in antibiotic resistance and associated molecular mechanisms. His recent work was focused on understanding colistin resistance patterns in the environment, particularly in water bodies.
Other Publications by Author:
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