Challis-Alkhalaf Group

A thread about how microbiologists persuaded a bacterium to make an exciting new antibiotic candidate - work by @challis-group.bsky.social @correlab.bsky.social and colleagues #MicroSky

Oh my gosh. This is... A thing. Please allow a microbiologist who has played with the microbe that makes this to waffle on for a bit in a short thread. (1)

What Rosalind Franklin truly contributed to the discovery of DNA’s structure Franklin was no victim in how the DNA double helix was solved. An overlooked letter and an unpublished news article, both written in 1953, reveal that she was an equal player.

What Rosalind Franklin truly contributed to the discovery of DNA’s structure. A really informative article, perfect for a weekend coffee read. www.nature.com/articles/d41...

Discovery of Late Intermediates in Methylenomycin Biosynthesis Active against Drug-Resistant Gram-Positive Bacterial Pathogens The methylenomycins are highly functionalized cyclopentanone antibiotics produced by Streptomyces coelicolor A3(2). A biosynthetic pathway to the methylenomycins has been proposed based on sequence analysis of the proteins encoded by the methylenomycin biosynthetic gene cluster and the incorporation of labeled precursors. However, the roles played by putative biosynthetic enzymes remain experimentally uninvestigated. Here, the biosynthetic functions of enzymes encoded by mmyD, mmyO, mmyF, and mmyE were investigated by creating in-frame deletions in each gene and investigating the effect on methylenomycin production. No methylenomycin-related metabolites were produced by the mmyD mutant, consistent with the proposed role of MmyD in an early biosynthetic step. The production of methylenomycin A, but not methylenomycin C, was abolished in the mmyF and mmyO mutants, consistent with the corresponding enzymes catalyzing the epoxidation of methylenomycin C, as previously proposed. Expression of mmyF and mmyO in a S. coelicolor M145 derivative engineered to express mmr, which confers methylenomycin resistance, enabled the resulting strain to convert methylenomycin C to methylenomycin A, confirming this hypothesis. A novel metabolite (premethylenomycin C), which readily cyclizes to form the corresponding butanolide (premethylenomycin C lactone), accumulated in the mmyE mutant, indicating the corresponding enzyme is involved in introducing the exomethylene group into methylenomycin C. Remarkably, both premethylenomycin C and its lactone precursor were one to two orders of magnitude more active against various Gram-positive bacteria, including antibiotic-resistant Staphylococcus aureus and Enterococcus faecium isolates, than methylenomycins A and C, providing a promising starting point for the development of novel antibiotics to combat antimicrobial resistance.

So cool. Greg Challis shows that a methylenomycin precursor is a better antibiotic than methylenomycin itself. This is in S.coelicolor A3(2)! Probably many similar examples yet to be discovered of pathways intermediates being useful, but consistently overlooked. #secmet

pubs.acs.org/doi/10.1021/...

Very happy to have been involved in the discovery of “pre-methylenomycin C lactone”, a promising new antibiotic from Streptomyces bacteria - #JACS
warwick.ac.uk/news/pressre...

Discovery of Late Intermediates in Methylenomycin Biosynthesis Active against Drug-Resistant Gram-Positive Bacterial Pathogens The methylenomycins are highly functionalized cyclopentanone antibiotics produced by Streptomyces coelicolor A3(2). A biosynthetic pathway to the methylenomycins has been proposed based on sequence an...

Check out our latest paper in the Journal of the American Chemical Society on the discovery of a new Streptomyces coelicolor antibiotic with potent activity against MRSA and multi-drug resistant Enterococci that has been hiding in plain sight for more than 50 years.
pubs.acs.org/doi/full/10....

Nitrogen deletion in the biosynthesis of HDAC-targeting anticancer drugs Small molecules play indispensable roles in living systems as hormones, membrane bilayer constituents, enzyme cofactors, metal chelators, and defensive chemicals. The exceptional structural diversity ...

Check out the latest version of our preprint on nitrogen deletion in HDAC-targetting anticancer drug biosynthesis. Amazing work by Xinyun Jian @monashuniversity.bsky.social, Jinlian Zhao @uni-of-warwick.bsky.social and colleagues in the Cryle and Fairlie labs.

www.biorxiv.org/content/10.1...

Speakers | emc2026

Lona Alkhalaf will speak about the discovery, structure, and mechanism of a cool new family of enzymes discovered by the group at the 29th Enzyme Mechanisms Conference.

www.enzymemechanismsconference.org/speakers

16th Australian Peptide Conference

Greg Challis will be presenting the group's latest insights into peptidyl epoxyketone biosynthesis at the 16th Australian Peptide Conference in beautiful Tasmania.

www.peptides2025.org

Interested in natural product producing microorganisms? 🦠 See you in Berlin... 😀

The names of panel members for the criteria-setting phase of REF 2029 have now been announced on our panels pages. 2029.ref.ac.uk/news/expert-...

Excited to announce our latest preprint, exploring the stereochemistry & antiviral properties of natural product MM46115 (pellemicin) against influenza. 🦠 💊 Big thanks to all co authors, including @afifahtasnim.bsky.social @craigpthomp.bsky.social and others. www.biorxiv.org/content/10.1...