Brian O. Bachmann

Brian O. Bachmann

@brianobachmann.bsky.social

Prof. Chemical Biology, PI the Vanderbilt Laboratory for Biosynthetic Studies. Posting natural product tilted human chemical biology, biosynthesis, synthetic biology, and discovery.

1K followers740 following128 posts

Brian O. Bachmann reposted

Nadine Ziemert
@nadineziemert.bsky.social

Congrats to @turgutmesut.bsky.social @canerbagci.bsky.social and Semih Erdoğmuş for the update and major improvement of ARTs-DB academic.oup.com/database/art... 🥳 Now also including fungal data and a much improved and more intuitive interface!! happy #targetdirectedgenomemining #secmet

academic.oup.comARTS-DB 2.0: an expanded database for target-directed genome mining across bacteria and fungiAbstract. The increasing prevalence of antimicrobial resistance requires efficient strategies to prioritize biosynthetic gene clusters (BGCs) that may enco
Brian O. Bachmann
@brianobachmann.bsky.social

In vitro reconstruction study providing cool new insights into "AT-less" PKS. Internal KSo domains for non-elongating modules. #natprod www.nature.com/articles/s41...

nature.comCondensation-independent intramodular translocation mechanism of the trans-AT polyketide synthase assembly line - Nature Chemical BiologyDecarboxylative condensation is essential for polyketide and fatty acid biosynthesis, yet the mechanism underlying nonelongating modules without this step remains elusive. Here the authors report a co...
Brian O. Bachmann
@brianobachmann.bsky.social

We then used thermal proteome profiling to measure the perturbation of protein stability on induction with SBLs. Interestingly, we found perturbation in RNA processing and splicing effected on brief incubation SBLs. This was confirmed by mRNASeq and alternative splicing analysis.

Brian O. Bachmann
@brianobachmann.bsky.social

Natural products containing beta-lactones are covalent protein modifiers, & their unknown mechanism and electrophilic nature got us curious about their mechanism. Using genome mining, and our single cell Multiplexed Activity Metabolomics, we identified a new producer and isolated a family of SBLs.

Brian O. Bachmann
@brianobachmann.bsky.social

We are pleased to share our new work in @pnas.org investigating the discovery, biosynthesis, and mechanistic investigation of a class of molecules we call spirocyclic beta-lactones! Skeetorial to follow. #natprod 🧪 www.pnas.org/doi/full/10....

pnas.orgPNASProceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Brian O. Bachmann reposted

Wildtype One
@wildtypeone.bsky.social

Replying to @brianobachmann.bsky.social

Measuring the effect of complex metabolite mixtures directly in primary patient cells bridges a long-standing gap between product discovery and clinical relevance Single-cell resolution adds mechanistic clarity that’s often missing in bulk Thanks for sharing @brianobachmann.bsky.social

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Brian O. Bachmann
@brianobachmann.bsky.social

After isolation, we then test the pure compounds against biopsied bone marrow cell mixtures from 4  genotyped patients diagnosed with cancer, and healthy PBMCs, to see how purified compounds affect both wild cancer cells and normal hematopoetic cells.

Brian O. Bachmann
@brianobachmann.bsky.social

This is determined again at the single cell level, this time even more multiplexed, using mass cytometry, which can observe dozens of markers per cell using monoisotopic metal tagged antibodies and ICP-MS detection. We see striking differences between patients.

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Brian O. Bachmann
@brianobachmann.bsky.social

We first use our platforms Multiplexed Activity Profiling & Multiplexed Activity Metabolomics for this workflow in extract and metabolite arrays. The output for activity in wells comes in the form of "Rothko plots" after debarcoding, which records the effects of metabolites in wells in single cells.

Brian O. Bachmann
@brianobachmann.bsky.social

After determining which metabolites in an metabolomic array (fraction library of 8 - 96 wells) in a single flow fun, we prioritize them for  isolation and structure elucidation. We identified two knows, siderochelin and isoquinocycline with very interesting cellular perturbations.

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Brian O. Bachmann
@brianobachmann.bsky.social

As described by graduate coworker Schares et al,the idea is to measure the effect of natural products in extracts and metabolomes against primary cells biopsied from patients diagnosed with cancer at single cell (ex vivo) resolution. This is accomplished using flow cytometry.

sciencedirect.comMultiplexed cytometry for single cell chemical biologyFlow cytometry has great potential for screening in translational research areas due to its deep quantification of cellular features, ability to colle…

Brian O. Bachmann reposted

Nature Portfolio
@natureportfolio.nature.com

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Communications Sustainability@commssustain.nature.com

🚗🔋A new look at 2023 US vehicles finds electric vehicles have lower life‑cycle greenhouse‑gas emissions than similar gas, diesel, and hybrid models, across all grid, climate, and battery‑lifetime scenarios. #EVs 🧪@ucdavisresearch.bsky.social@natureportfolio.nature.com www.nature.com/articles/s44...

nature.comElectrifying light vehicles in the United States shows emission reduction potential for all vehicle types and powertrains - Communications SustainabilityElectric vehicles could cut emissions more than gasoline and hybrid models under varied climates, electricity grids, and battery lifetimes, with the largest gains from light trucks, finds a life-cycle...
Brian O. Bachmann
@brianobachmann.bsky.social

A new entry in ML prediction of adenylation domain selectivity in nonribosomal peptide synthetases using a protein language model. Interestingly, it boasts 92% accuracy. Compare to the 25 year old Stachelhaus code (a type of homology modeling) at 89% accuracy. #secmet

pubs.acs.orgNRPStransformer, an Accurate Adenylation Domain Specificity Prediction Algorithm for Genome Mining of Nonribosomal PeptidesNonribosomal peptides serve as pivotal sources for drug discovery. Accurate prediction of the substrate specificity of adenylation domains in nonribosomal peptide synthetases is crucial for genome mining of nonribosomal peptides, yet current prediction methods fall short in accuracy. In this work, we analyzed 4,100 adenylation domains from documented nonribosomal peptide synthetases and found that the flavodoxin-like subdomain universally governs substrate specificity in all bacterial adenylation domains and that its phylogenetic analysis can correlate the sequences of adenylation domains and their substrate specificity. Leveraging the sequences within the flavodoxin-like subdomain, we developed a substrate specificity prediction algorithm using a protein language model, achieving 92% overall prediction accuracy for 43 frequently observed amino acids, significantly improving the prediction reliability. The efficacy of our prediction tool was validated through targeted genome mining, which led to the discovery of novel antimicrobial peptides. Our work lays a foundation to understand the sequence-to-function relationship of the bacterial adenylation domain and will facilitate the exploitation of nonribosomal peptides. NRPStransformer is available at http://www.nrpstransformer.cn.

Brian O. Bachmann reposted

Louis-Marie Bobay
@lbobay.bsky.social

Our latest paper is out with @adiop.bsky.social and @gmdouglas.bsky.social. We analyzed the extent of homologous recombination between bacterial species (introgression) and how it affects species borders (it can vary a lot depending on the approach used to classify species!). rdcu.be/eQAMf

rdcu.beIntrogression impacts the evolution of bacteria, but species borders are rarely fuzzyNature Communications - It is commonly thought that bacterial species borders tend to be fuzzy, due to frequent exchange of DNA. Here, Diop et al. quantify the patterns of gene flow between core...
Brian O. Bachmann
@brianobachmann.bsky.social

"Cobaltribin", a cobalt containing complex isolated from a streptomyces (3.1 mg from 40 × 0.5 L). #secmet, pubs.acs.org/doi/10.1021/...

pubs.acs.orgDiscovery and Biosynthetic Interrogation of a Cobalt-Containing Terpene-Polyketide-Nonribosomal Peptide Tribrid with Anticoronavirus ActivityThe structural complexity of natural products arises from the complexity of their biosynthetic pathways and directly contributes to their biological activities. Guided by this principle, we screened 5...

Brian O. Bachmann reposted

Nadine Ziemert
@nadineziemert.bsky.social

Happy to share our newest manuscript about the discovery and hererologous expression of metanodin, a new lassopeptide with unprecedented structural features directly from soil metagenomes. pubs.acs.org/doi/full/10.... #secmet #lassopeptides #syntheticbiology

pubs.acs.orgDiscovery and Heterologous Expression of the Soil Metagenome-Derived Lasso Peptide Metanodin with an Unprecedented Ring StructureCulture-independent metagenomic approaches have proven to be effective tools for identifying previously hidden biosynthetic gene clusters (BGCs) encoding novel natural products with potential medical relevance. However, producing these compounds remains challenging as metagenomic BGCs often originate from organisms phylogenetically distant from available heterologous hosts. Lasso peptides, a subclass of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, exhibit diverse bioactivities, yet no lasso peptide has previously been discovered directly from a metagenome. Here, we report the discovery and heterologous expression of the first soil metagenome-derived lasso peptide. Expression of its biosynthetic gene cluster in Escherichia coli, followed by mass spectrometry analysis, strongly supported the predicted amino acid sequence and lasso structure of the peptide. Notably, this lasso peptide is the first to feature asparagine as the ring-forming residue at position one. Taxonomic analysis of the corresponding BGC identified an uncultivated member of the Steroidobacterales family (Gammaproteobacteria) as the closest known relative of the potential native host. These findings underscore the potential of metagenomic genome mining to reveal structurally novel RiPPs and to expand our understanding of the natural diversity of lasso peptides.
Brian O. Bachmann
@brianobachmann.bsky.social

Fantastic: 44 new pyrrolobenzodiazepine's via an engineered single module reductase terminated NRPS system #natprod #secmet

Andrew Gulick@amgulick-lab.bsky.social

Happy to report our latest. Here, Monica used structure-guided mutants of the tilimycin/tilivalline NRPS to produce analogs from alternate building blocks. Several analogs of the pyrrolobenzodiazepine tilimycin were isolated and may show higher activity. pubs.acs.org/doi/10.1021/...

pubs.acs.orgProtein Engineering of Biosynthetic Enzymes Unlocks Libraries of Bioactive Tilimycin AnalogsNatural products continue to inspire therapeutic innovation due to their structural complexity and biological potency. Pyrrolobenzodiazepines (PBDs), known for antitumor activity, function by covalently binding to guanine bases in DNA, a mechanism that is inherently species-agnostic. However, their potential as antibiotics remains underexplored as modest antibiotic activity is commonly seen with this class of compounds. Here, we produce analogs of tilimycin and tilivalline, two PBDs produced by the gut microbe Klebsiella oxytoca. We mutated NpsA, the nonribosomal peptide synthetase (NRPS) pathway protein responsible for initiating biosynthesis through adenylation of 3-hydroxyanthranilic acid on the pathway to form tilimycin and tilivalline, to enhance promiscuity with substrate analogs. Using structure and informatics-guided mutagenesis, we developed a rapid screening method to identify compatible enzyme-building block combinations to generate a panel of tilimycin and tilivalline analogs. We identified compounds that possess the ability to inhibit DNA polymerase and that show growth inhibitor activity with a DNA-repair mutant of E. coli. This work demonstrates the feasibility of NRPS reprogramming to use biocatalytic approaches to access non-natural derivatives with antibiotic potential and highlights tilimycin analogs as candidates for Gram-negative antibacterial development.
Brian O. Bachmann
@brianobachmann.bsky.social

This gives the George Gershwin song “Let’s call the Whole Thing Off” a whole new spin. You like potato and I like potato You like tomato and I like tomato Potato, potahto, tomato, tomahto Let's call the whole thing off 🧪

Alexa Robles-Gil@alexaroblesgil.bsky.social

An ancient hybrid of tomatoes and potato-like plants may have given rise to the modern spud, a new study suggests. www.nytimes.com/2025/07/31/s...

nytimes.comWhat’s a Potato? A Nine-Million-Year-Old Tomato.
Brian O. Bachmann
@brianobachmann.bsky.social

We put together this protocol in part to encourage broader adoption of Multiplexed Activity Metabolomics, an engine for functional metabolomics of all types including specialized metabolite discovery. We enjoy knowing if metabolite is active before isolating it, and so should you! #natprod

sciencedirect.comMultiplexed cytometry for single cell chemical biologyFlow cytometry has great potential for screening in translational research areas due to its deep quantification of cellular features, ability to colle…