Microbial Bioactives
Microbial Bioactives | Online ISSN 2209-2161
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Volume 9 Number 1 2026
REVIEWS (Open Access)
Illuminating Biological Dark Matter: Integrating Metagenomics, Synthetic Biology, and AI to Unlock Microbial and Genomic Potential for Therapeutics and Biotechnology
Yue Li 1, Shunqi Liu 2 *
Microbial Bioactives 9 (1) 1-8 https://doi.org/10.25163/microbbioacts.9110627
Submitted: 13 February 2026 Revised: 01 April 2026 Accepted: 08 April 2026 Published: 10 April 2026
Abstract
The exploration of microbial and human genomic "dark matter" has transformed biotechnology, shifting the focus from merely reading genetic codes to actively engineering and harnessing them for sustainable solutions and human health. Over 99% of microorganisms remain uncultured, representing vast reservoirs of novel natural products (NPs) and enzymes that can be accessed through culture-independent metagenomics. Function-based, sequencing-based, and single-cell metagenomic approaches enable the discovery of bioactive compounds such as turbomycins, fasamycins, and cadasides, which hold promise against multidrug-resistant pathogens. Parallel advances in synthetic biology have established robust chassis organisms, including Saccharomyces cerevisiae and fast-growing cyanobacteria, optimized for industrial production of biofuels, chemicals, and bioplastics. Artificial intelligence (AI) and machine learning further refine these platforms, providing predictive models for bioprocess optimization, biomass accumulation, and metabolic engineering. In clinical contexts, proteogenomics integrates DNA, RNA, and protein-level data to identify therapeutic targets and overcome drug resistance in diseases such as colorectal cancer. The ongoing evolution of HIV-1 illustrates the challenge of viral diversity, highlighting the role of next-generation sequencing, CRISPR-based gene editing, and biosensor-enabled surveillance in precision medicine. Gut microbiota manipulation, through fecal microbiota transplantation and engineered probiotics, represents a frontier for addressing systemic and metabolic disorders. This systematic review synthesizes quantitative data from these diverse fields, emphasizing the synergy between metagenomics, synthetic biology, and AI, and provides a meta-analytic framework to evaluate their translational potential for therapeutics, industrial biotechnology, and personalized medicine.
Keywords: Metagenomics; Synthetic Biology; Artificial Intelligence; Microbial Dark Matter; Proteogenomics; HIV-1; Gut Microbiota; Natural Products
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