iiinova — where your digital self keeps evolving

Brian O. Bachmann @brianobachmann.bsky.social · 31/03/2026

Congrats to Katie et al and special thanks to our collaborators in the Plate lab at Vanderbilt (TPP), and Irish Lab at U Colorado (flow)

Picture of Elvis saying thank you very much.

100

Brian O. Bachmann @brianobachmann.bsky.social · 31/03/2026

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.

TPP Volcano plot showing proteins stabilized and destabilized by induction with SBLs

110

Brian O. Bachmann @brianobachmann.bsky.social · 31/03/2026

We used a flow cytometry to investigate potential mechanistic possibilities of SBLs e induction showing inhibition of phospho-signaling related to nutrient signaling.

Cell signaling pathway related to nutrient sensing, highlighting markers assayed by flow cytometry

110

Brian O. Bachmann @brianobachmann.bsky.social · 31/03/2026

This facilitated structure-activity relationship, verifying their potency against leukemia cell lines and the importance of the beta-lactone for cytotoxicity.

Structures of SBLs isolated from a single Streptomyces

100

Brian O. Bachmann @brianobachmann.bsky.social · 31/03/2026

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.

A close up of Multiplexed Activity Metabolomics showing debarcoded flow cytometry generated "Rothko" plots

100

Brian O. Bachmann @brianobachmann.bsky.social · 31/03/2026

Spirocyclic beta-lactones (SBLs) are a beautiful class of molecules produced by bacteria with a beta-lactone fused to a gamma-lactam with potent and selective activity against various cancer cell lines

Structures various showing SBLs from bacteria

100

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

We believe this method provides a way to start to link genotypes of cancer to their responses to small molecules, in this case secondary metabolites! Deep thanks to my partner in crime, cytometric wizard @jonathanirish.bsky.social at U Colorado, and P. Brent Ferrell, MD and Vanderbilt.

$Multiplexed Activity Metabolomic Overview showing the generation and fractionation of extracts into well plates, the addition of patient derived cells from a biopsy.$

120

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

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.

tSNE plot of single cell data from compound exposure.

110

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

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.

Schematic showing patients on the left, molecules tested against bone marrow in the middle, and a cartoon of bone marrow cells.

110

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

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.

MAM plot for identification of isoquinocyclin

MAM plot for identification of siderochelin

100

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

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.

Painting by Mark Rothko, which looks like our data format for debarcoded cells.

Scatter plots of single cell data in red and black resembling a Rothko painting.

110

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

This dovetails with 'genome mining' workflows which can derisk discovery. In these case studies, we use gifted actinomycetes isolated from caves as a source material, but this can be applied to extracts and metabolomic arrays from any source. www.micropublication.org/journals/bio...

Pictures of cave walls, isolated microbes, and genomic analysis

100

Brian O. Bachmann @brianobachmann.bsky.social · 25/02/2026

We are delighted to share our vision in #RSCChemBioy of how to incorporate natural product discovery (and any drug discovery) into the framework of personalized medicine - drug discovery using patients, but not in patients! #natprod #secmet pubs.rsc.org/en/content/a...

1145

Brian O. Bachmann @brianobachmann.bsky.social · 28/12/2025

Cool compounds, Leshmania activitiesw/ good therapeutic index, and nice structure work. Hard work: "A culture (322 × 10 mL, 3.2 L) of the strain was obtained in the FR23 medium... 0.6 - 3.2 mg isolated of several analogs". #secmet pubs.acs.org/doi/10.1021/...

TOC image of a large polyol polyketide coming from a cultured streptomyces and a large polyketide synthase biosynthetic gene cluster, with compounds showing activity in glowing fluorescent cells.

011

Brian O. Bachmann @brianobachmann.bsky.social · 28/10/2025

The Discovery of Complex Heterocycles from Millipede Secretions, fantastic work from the Mevers group that I saw the full story from at SERMACS this week. pubs.acs.org/doi/10.1021/... #secmet

Picture of white millipedes next to an HPLC chromatogram, with one blue peak and five red peaks above blue and red chemical structures describing scaffold of the molecules comprising the peaks. Andrognathanols (blue) are 6,6,6,5-tetracyclic bridged alkaloids and andrognathines are 5,6-fused bicyclic alkaloids.

030

Brian O. Bachmann @brianobachmann.bsky.social · 13/06/2025

Dracomicins, Hybrid Oligosaccharide–Nonribosomal Peptide Antibiotics from Amycolatopsis Species pubs.acs.org/doi/10.1021/...

On the left, a picture of a Petri dish showing an amycalotopsis from which comes in the center, a cartoon dragon and under the dragon the molecules called Dracomycins, which are drawn in the shape of the dragon. On the right a petri dish showing a cartoon of zones of inhibition.

0114

Brian O. Bachmann @brianobachmann.bsky.social · 18/11/2024

From the Jensen lab: Pattern-based genome mining guides discovery of the antibiotic indanopyrrole A from a marine streptomycete www.biorxiv.org/content/10.1...

0124

Brian O. Bachmann @brianobachmann.bsky.social · 12/12/2023

👀 “S. coelicolor encodes three “umbrella particles” with distinct toxin and lectin composition, and supernatant containing these toxins specifically and potently inhibits the growth of select Streptomyces species.” Not #secmet, but cool S.coel technology. www.biorxiv.org/content/10.1...

062

Brian O. Bachmann @brianobachmann.bsky.social · 30/10/2023

Wow! A beautiful hexacyclic sesterterpene via in vitro reaction with a cloned terpene cyclase from Streptomyces subrutilus #secmet onlinelibrary.wiley.com/doi/10.1002/...

040

Brian O. Bachmann @brianobachmann.bsky.social · 18/10/2023

Structure and Function of the alpha-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase #secmet onlinelibrary.wiley.com/doi/10.1002/...

010

Brian O. Bachmann @brianobachmann.bsky.social · 15/10/2023

#secmet folks : a teach-in in honor of Chris Walsh. All students and post-docs encouraged to attend. This is an outstanding speaker list inspired a great scientist & teacher.

284

Brian O. Bachmann @brianobachmann.bsky.social · 27/09/2023

Cave chemistry collection with grad students.

160

Brian O. Bachmann @brianobachmann.bsky.social · 27/09/2023

Novel Biocatalysts from Specialized Metabolism from Hertweck and Co. Chemsky 🧪 onlinelibrary.wiley.com/doi/abs/10.1...

030

Brian O. Bachmann @brianobachmann.bsky.social · 20/09/2023

Cell-Free Synthesis of Natural Compounds from Genomic DNA of Biosynthetic Gene Clusters. Production of the NRPS BpsA from Streptomyces lavendulae and the RXP producer Xenorhabdus KJ12.1 pubs.acs.org/doi/10.1021/...

060

Brian O. Bachmann @brianobachmann.bsky.social · 24/08/2023

Enzyme tacks bromine or iodine onto terminal alkynes cen.acs.org/biological-c...

011

Brian O. Bachmann @brianobachmann.bsky.social · 21/08/2023

Global warming + Prometheus, a toxic combination to nature, perhaps a lesson for today? 🧪 www.science.org/doi/10.1126/science…

000

Brian O. Bachmann @brianobachmann.bsky.social · 07/08/2023

Breaking news: Actual 'evil genius' plan to blot out the sun! 🧪 www.pnas.org/doi/10.1073/pnas.23074…

000

Brian O. Bachmann @brianobachmann.bsky.social · 06/08/2023

Embarrassed I did not know, and delighted to learn, that there are over 300 organoarsenic natural products. Bisenarsan is the first actinomycete-derived arsenic-containing secondary metabolite to be characterized. 🧪 pubs.acs.org/doi/10.1021/jacs.3c049…

000