PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 11386362

Engineering biodiversity with type II polyketide synthase genes.

B S Moore·J Piel
View original source ↗Export metadata ↓

Abstract

A very important task in the ongoing search for new clinically useful drugs is the generation of large numbers of structurally diverse compounds. The emerging field of combinatorial biosynthesis, in which nature's chemical capabilities are exploited in a combinatorial 'mix-and-match' fashion, has generated libraries of novel molecules representing great structural diversity which are not available naturally or readily generated through (combinatorial) synthesis. Novel polyketides have been generated by manipulating type II iterative polyketide synthase (PKS) systems that express a variety of combinations of a minimal PKS with ketoreductases, cyclases, and other tailoring enzymes, resulting in a set of design rules to rationally engineer new metabolites. Engineering studies with the Streptomyces coelicolor whiE (spore pigment) and the 'Streptomyces maritimus' enterocin type II PKS provide additional insight on designing diverse assemblies of aromatic, as well as nonaromatic, polyketides.

Explore related subjects

Anti-Bacterial AgentsEcosystemGenetic EngineeringMultienzyme ComplexesSpores, BacterialStreptomycesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

B S Moore, J Piel. 2000. Engineering biodiversity with type II polyketide synthase genes.. https://doi.org/10.1023/a%3A1010273224820

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

Total Synthesis and Structural Revision of Rhabdobranin Reveals a Cryptic Gram-Negative Antibiotic.

Gram-negative bacteria present a major clinical challenge but also remain an underexplored source of antibacterial natural products. Resistance-guided genome mining of the entomopathogenic symbiont Xenorhabdus identified the rdb biosynthetic gene cluster, which encodes a putative prodrug antibiotic, pre-rhabdobranin. However, the inability to isolate the proposed active metabolite, rhabdobranin, has prevented direct functional evaluation. Here we report a convergent total synthesis of the proposed structure of pre-rhabdobranin B, which revealed a stereochemical misassignment at the N-terminal arginine residue. Synthesis of both rhabdobranin epimers showed that, although they are nearly indistinguishable by standard analytical methods, inversion at this single stereocenter has a pronounced effect on antibacterial activity. Biological evaluation of the revised rhabdobranin structure revealed potent antibacterial activity against Gram-negative pathogens, including WHO critical-priority carbapenem-resistant Klebsiella pneumoniae. Cellular and biochemical profiling implicated inhibition of protein biosynthesis as its principal antibacterial mechanism. We further show that the GNAT-family acetyltransferase RdbK N-acetylates rhabdobranin, attenuating its activity and establishing a secondary self-resistance mechanism. These findings validate resistance-gene-guided discovery in Gram-negative symbionts as a strategy for uncovering cryptic antibiotics and identify rhabdobranin as a promising scaffold for Gram-negative antibiotic development.

Anti-Bacterial Agents↗
PubMed2026

Environmental antibiotic contamination and AMR: Integrating pathways, impacts, and artificial intelligence-driven mitigation.

The widespread contamination of the environment with antibiotic residues is a significant factor contributing to the global crisis of antimicrobial resistance (AMR). Antibiotics from various sources, such as effluents from municipal and hospital wastewater treatment plants, agricultural runoffs, discharges from pharmaceutical manufacturing and improper disposal of expired or unused medicines, create selective pressures in the spread of antibiotic resistance genes. These environmental reservoirs act as hotspots for horizontal gene transfer, facilitating the emergence of multidrug-resistant pathogens. Conventional detection methods including culture-based assays, chromatographic quantification, and molecular diagnostics, provide essential insights but are limited by low throughput, reduced sensitivity to new Antibiotic Resistance Genes, and challenges in real-time monitoring across complex environments. Recent advances, such as whole-genome sequencing, metagenomics, and biosensor-based detection, help to address these gaps by enabling more comprehensive surveillance of the resistome. Artificial intelligence further enhances these approaches by improving data interpretation and pattern recognition, thus complementing traditional and molecular methods rather than replacing them. This review examines the pathways of environmental antibiotic contamination, ecological and health impacts of AMR, and limitations of conventional detection methods. It aims to clarify how these pathways contribute to the AMR crisis, assess the effectiveness of existing surveillance techniques, and identify gaps in current research.

Anti-Bacterial Agents↗
PubMed2026

Discovery of Glycosylated β-Amino Acid-Containing Macrolactams from Nonomuraea sp. 0L2P via Genome Mining.

β-Amino acid-containing macrolactams (β-AACMs) are a class of bioactive natural products characterized by nitrogen-containing starter units within polyketide-derived macrocycles. Here, we report four previously undescribed macrolactams, gruelactams A-D (1-4), from Nonomuraea sp. 0L2P, discovered through an integrated approach combining genome mining, 15N-labeling, and antibacterial screening. Their planar structures were elucidated by comprehensive spectroscopic analyses, including 1D and 2D NMR and HRESI-MS, and their configurations were partially assigned based on ROESY data and bioinformatic analysis. Genome sequencing and antiSMASH analysis identified a putative type I polyketide synthase (PKS) biosynthetic gene cluster, enabling the proposal of a biosynthetic pathway. Bioactivity assays showed that gruelactam D (4) exhibits antibacterial activity against Bacillus cereus and Staphylococcus aureus, with MIC values of 8 and 16 μg/mL, respectively. These findings expand the chemical diversity of β-AACMs and demonstrate the utility of genome-guided approaches for discovering bioactive natural products from rare actinomycetes.

Anti-Bacterial Agents↗