Primed for Discovery DOI Creative Commons
Allison S. Walker, Jon Clardy

Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Antibiotics are essential components of current medical practice, but their effectiveness is being eroded by the increasing emergence antimicrobial-resistant infections. At same time, rate antibiotic discovery has slowed, and our future ability to treat infections threatened. Among Christopher T. Walsh's many contributions science was his early recognition this threat potential biosynthesis─genes mechanisms─to contribute solutions. Here, we revisit a 2006 review Walsh co-workers that highlighted major challenge in natural product discovery: daunting odds for identifying new naturally occurring antibiotics. The described strategies mitigate challenge. These have been used extensively community years since resulted some promising discoveries. Despite these advances, rarity novel products remains barrier discovery. We compare discovering antibiotics process prime numbers, which also challenging find an essential, if underappreciated, element modern life. propose inclusion filters functional compounds pipeline key discovery, recent advances enable this, discuss remaining challenges need be addressed make sustainable future.

Language: Английский

Targeted genome mining with GATOR-GC maps the evolutionary landscape of biosynthetic diversity DOI Creative Commons
José D. D. Cediel-Becerra, Andrés Cumsille, Sebastian Guerra

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Gene clusters, groups of physically adjacent genes that work collectively, are pivotal to bacterial fitness and valuable in biotechnology medicine. While various genome mining tools can identify characterize gene they often overlook their evolutionary diversity, a crucial factor revealing novel cluster functions applications. To address this gap, we developed GATOR-GC, targeted tool enables comprehensive flexible exploration clusters single execution. We show GATOR-GC identified diversity over 4 million similar experimentally validated biosynthetic (BGCs) other fail detect. highlight the utility previously uncharacterized co-occurring conserved potentially involved mycosporine-like amino acid biosynthesis mapped taxonomic patterns genomic islands modify DNA with 7-deazapurines. Additionally, its proximity-weighted similarity scoring, successfully differentiated BGCs FK-family metabolites (e.g., rapamycin, FK506/520) according chemistries. anticipate will be assess for targeted, exploratory, mining. is available at https://github.com/chevrettelab/gator-gc .

Language: Английский

Citations

1
Enediyne natural product biosynthesis unified by a diiodotetrayne intermediate DOI
Chun Gui, Edward Kalkreuter, Lukas Lauterbach

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(9), P. 1210 - 1219

Published: June 3, 2024

Language: Английский

Citations

6
Chalkophomycin Biosynthesis Revealing Unique Enzyme Architecture for a Hybrid Nonribosomal Peptide Synthetase and Polyketide Synthase DOI Creative Commons
Long Yang, Liwei Yi,

Bang Gong

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(9), P. 1982 - 1982

Published: April 25, 2024

Chalkophomycin is a novel chalkophore with antibiotic activities isolated from Streptomyces sp. CB00271, while its potential in studying cellular copper homeostasis makes it an important probe and drug lead. The constellation of N-hydroxylpyrrole, 2H-oxazoline, diazeniumdiolate, methoxypyrrolinone functional groups into one compact molecular architecture capable coordinating cupric ions draws interest to unprecedented enzymology responsible for chalkophomycin biosynthesis. To elucidate the biosynthetic machinery production, chm gene cluster S. CB00271 was identified, involvement biosynthesis confirmed by replacement. localized ~31 kb DNA region, consisting 19 open reading frames that encode five nonribosomal peptide synthetases (ChmHIJLO), modular polyketide synthase (ChmP), six tailoring enzymes (ChmFGMNQR), two regulatory proteins (ChmAB), four resistance (ChmA′CDE). A model proposed based on assignments sequence analysis structure modelling, further supported analogy over 100 chm-type clusters public databases. Our studies thus set stage fully investigate engineer analogues through synthetic biology approach.

Language: Английский

Citations

4
Targeted genome mining for natural product discovery DOI
José D. D. Cediel-Becerra, Marc G. Chevrette

Methods in enzymology on CD-ROM/Methods in enzymology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Chalkophomycin Biosynthesis Revealing Unique Enzyme Architecture for a Hybrid Nonribosomal Peptide Synthetase and Polyketide Synthase DOI Creative Commons
Long Yang, Liwei Yi,

Bang Gong

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 14, 2024

Abstract Chalkophomycin is a novel chalkophore with antibiotic activities isolated from Streptomyces sp. CB00271, while its potential in studying cellular copper homeostasis makes it an important probe and drug lead. The constellation of N -hydroxylpyrrole, 2 H -oxazoline, diazeniumdiolate, methoxypyrrolinone functional groups into one compact molecular architecture capable to coordinate cupric ion draws interest unprecedented enzymology responsible for chalkophomycin biosynthesis. To elucidate the biosynthetic machinery production, chm gene cluster S. CB00271 was identified, involvement biosynthesis confirmed by replacement. localized ∼31 kb DNA region, consisting 19 open reading frames that encode five non-ribosomal peptide synthetase (ChmHIJLO), modular polyketide synthases (ChmP), six tailoring enzymes (ChmFGMNQR), two regulatory proteins (ChmAB), four resistance (ChmA′CDE). A model proposed based on assignments sequence analysis structure modelling, further supported analogy over 100 -type clusters public databases. Our studies thus set stage fully investigate engineer analogues through synthetic biology approach.

Language: Английский

Citations

2
Synthetic-bioinformatic natural product-inspired peptides DOI Creative Commons
Samantha Nelson, Elizabeth I. Parkinson

Natural Product Reports, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Synthetic-bioinformatic natural product inspired peptides ( syn -BNPs) are predicted from biosynthetic gene clusters that synthetically accessed. This method enables easier access to product-like for bioactivity screening.

Language: Английский

Citations

2
Primed for Discovery DOI Creative Commons
Allison S. Walker, Jon Clardy

Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Antibiotics are essential components of current medical practice, but their effectiveness is being eroded by the increasing emergence antimicrobial-resistant infections. At same time, rate antibiotic discovery has slowed, and our future ability to treat infections threatened. Among Christopher T. Walsh's many contributions science was his early recognition this threat potential biosynthesis─genes mechanisms─to contribute solutions. Here, we revisit a 2006 review Walsh co-workers that highlighted major challenge in natural product discovery: daunting odds for identifying new naturally occurring antibiotics. The described strategies mitigate challenge. These have been used extensively community years since resulted some promising discoveries. Despite these advances, rarity novel products remains barrier discovery. We compare discovering antibiotics process prime numbers, which also challenging find an essential, if underappreciated, element modern life. propose inclusion filters functional compounds pipeline key discovery, recent advances enable this, discuss remaining challenges need be addressed make sustainable future.

Language: Английский

Citations

0