The microorganism is a major source for biomedically important medicinal agents since most pharmaceutical drugs are either directly biosynthesized by microorganisms or chemically synthesized and modified based on the structure of microbial metabolites. Currently, approximately <1% of bacteria exist on Earth could be cultured under laboratory condition. These cultivatable bacteria have long been a source of antibiotics to combat illnesses and diseases. Unfortunately, the introduction of novel drugs into clinical application has almost always led to the development of resistance to those drugs, which shockingly decreases the drug shelf-life. To address this challenge, scientists decide to turn to the “dark matters” by either diging out the full-potential of cultured bacteria or exploring the uncultivable bacteria. Genome sequencing and genome mining began to shed some light on those dark matters, allowing scientists to reveal how some of potential drugs are biosynthesized by microbial DNA.

In the present thesis, I focused on one class of natural products – nonribosomal peptides that are biosynthesized from the nonribosomal peptide synthetase assembly line. Based on the information of genome sequencing we identified two domains on the assembly line that involved in antibiotic resistance. Following the genome mining and networking analysis of over 6,000 bacteria genomes, we eventually illustrated a universal peptide antibiotics resistance mechanism that targets at D-amino acid residues. Also...[ Read more ]

The microorganism is a major source for biomedically important medicinal agents since most pharmaceutical drugs are either directly biosynthesized by microorganisms or chemically synthesized and modified based on the structure of microbial metabolites. Currently, approximately <1% of bacteria exist on Earth could be cultured under laboratory condition. These cultivatable bacteria have long been a source of antibiotics to combat illnesses and diseases. Unfortunately, the introduction of novel drugs into clinical application has almost always led to the development of resistance to those drugs, which shockingly decreases the drug shelf-life. To address this challenge, scientists decide to turn to the “dark matters” by either diging out the full-potential of cultured bacteria or exploring the uncultivable bacteria. Genome sequencing and genome mining began to shed some light on those dark matters, allowing scientists to reveal how some of potential drugs are biosynthesized by microbial DNA.

In the present thesis, I focused on one class of natural products – nonribosomal peptides that are biosynthesized from the nonribosomal peptide synthetase assembly line. Based on the information of genome sequencing we identified two domains on the assembly line that involved in antibiotic resistance. Following the genome mining and networking analysis of over 6,000 bacteria genomes, we eventually illustrated a universal peptide antibiotics resistance mechanism that targets at D-amino acid residues. Also with the genome sequence in hand, we successfully assembled a biosynthetic pathway of a promising anti-neoplastic drug ex-situ. This assembly flowchart combinined several cutting-edge technologies which could be routinely practiced in future biosynthesis related study.