Thread by @CarstenPeukert

#MyFirstChemSci 🙌🏼
Are you an antibiotic targeting RNA-P? You just got an upgrade! We used the microbial iron transport machinery to enhance potency and improve accumulation into bacteria, where cleavable linkers release.
tinyurl.com/3chw8pnt @ChemicalScience

A 🧵: (1|n)

We found a way to enhance the potency of antibiotics targeting RNAP, rifamycins but also Corallopyronin A & Sorangicin A, by exploiting microbial iron transport to improve drug translocation across bacterial membranes using bacterial iron chelators- #siderophores. (2|n)

Gram-negative bacteria pose a unique challenge, due to their double membrane structure for antibiotic uptake e.g. for RNA-P inhibitors needing to reach the cytosol. But with innovative, targets approaches we can enhance their antimicrobial activity and overcome this hurdle. (3|n)

Cleavable linkers were used to release payloads inside the bacteria for unperturbed target binding. Our conjugates with the quinone trimethyl lock (Miller et al) proofed superior, providing up to 32-fold increase in antibiotic activity compared to the free payloads. (4|n)

Imagine a smart drug delivery system that uses a cleavable molecular entity to release antibiotics only when and where they are needed. That's the power of the cleavable linker technology. #drugdelivery (5|n)

Experiments with E. coli KO mutants showed that translocation and antibiotic effects were conferred by multiple outer membrane receptors & the motor protein TonB. = essential for activity. (6|n)

Our study proves how active transport and intracellular release can boost the potency of existing antibiotics against resistant Gram-negative pathogens. Have a peak inside 📣 please. (7|n)

Siderophores are amazing molecules that enable bacteria to scavenge iron from their environment, but they can also be utilised for novel diagnostic & therapeutic strategies against MDR pathogens. Read more below about how science is turning nature's tools against bacteria. (8|n)

This was pioneered by Marvin J. Miller's research on siderophores with developments in siderophore & linker (TML) synthesis led to the development of novel antibiotics with potent activity against Gram-negative pathogens.
tinyurl.com/bdcfrsts
tinyurl.com/5edvvuzh
(9|n)

Elisabeth Nolan's work on siderophore-antibiotic conjugates has opened up new avenues for treatment of bacterial infections, using the natural Enterobactin & Salmochelin to deliver b-lactam & Pt(IV) to uropathogenic E. coli
tinyurl.com/mr326mxc
tinyurl.com/4rvxk9zk (10|n)

We have expanded those great foundations for diagnostic & therapeutic application - link👇🏼:
- tinyurl.com/45pt3ce9
- tinyurl.com/32wa5brp
- tinyurl.com/48tynt8t

Thanks to all co-authors for their dedication & creativity! You are awesome & this is a massive team effort. 🥳
@BronstrupLab @AnnaCVetter @Helmholtz_HZI @DZIF_ @LeibnizUni

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