Adam Fountain

CDC leaders who resigned said RFK Jr. undermined vaccine science, risking lives As the CDC reels from the firing of its director, HHS Secretary Robert F. Kennedy Jr. told Fox News the agency is “in trouble and we need to fix it.”

Three senior CDC leaders who resigned told The Post they were asked to participate in an unscientific vaccine recommendation process that they believe could harm the health of Americans.

Our latest work, in collaboration with the terrific @kashishsingh.bsky.social in the Carter lab @mrclmb.bsky.social is out. So proud of this study and everyone involved...

🦠 NEW VIDEO 🦠

The molecular biology of how Mycobacterium Tuberculosis evades the immune system so well.

Starting with this simulation of a full outer envelope of m.TB--let's explore how the deadliest & most persistent human pathogen completely hacks our immune response. #molecularbiology

(8/8) I am incredibly grateful to everyone who made this work possible @medcambridge.bsky.social @mrclmb.bsky.social ‬@cambiochem.bsky.social

Thanks to Lalita, Ben and Meindert for their guidance and support. Jan + Tanmay for their EM wizardry and all members of the Ramakrishnan/Luisi labs
#ENDTB

(7/8) Worryingly, we found variants in MmpL5 that increase bedaquiline resistance. These variants haven’t been seen clinically… so far

Bedaquiline is a drug the world cannot afford to lose

We hope this will prompt urgent development of efflux-avoiding BDQ derivatives and new efflux pump inhibitors

(6/8) Using three independent genetic approaches, we identified variants in MmpL5 that both increase and decrease bedaquiline efflux. These variants converge on a site the lower periplasmic cavity of MmpL5 that we propose is the binding site of bedaquiline.

(5/8) @janboehning.bsky.social and @tbharat-lab.bsky.social ‬ did cryo-ET on Mtb. We find that the coiled-coil domain is only long enough to reach the Peptidoglycan-Arabinogalactan layer. A strongly conserved surface at the tip of MmpL5 hints at the presence of an elusive mycomembrane partner 🤔

(4/8) MmpL5 proteins often have a puzzling 13 nm long coiled coil inserted in their periplasmic domain that is essential for efflux.

Using AlphaFold2, we found that this domain forms an unusual methionine-lined tube to transport substrates across the periplasm.

(3/8) Surprisingly, we found that the trimer interface is mediated by phospholipids (which might explain why purifying this had proved so challenging 😥). The acpM protein that co-purifies with MmpL5 sandwiches its Phosphopantetheine group into the subunit interface…

(2/8) Our cryo-EM structure revealed that MmpS5L5 has a novel trimeric architecture distinct from the classic AcrAB-TolC pumps found in Gram-negative bacteria.

Mycobacteria always like to do things differently…

Structural and functional analysis of the Mycobacterium tuberculosis MmpS5L5 efflux pump presages a pathway to increased bedaquiline resistance Bedaquiline, an antitubercular drug that targets ATP-synthase, is a key component of a new oral drug regimen that has revolutionized the treatment of multi drug resistant tuberculosis. Clinical bedaqu...

Bedaquiline resistance driven by the MmpS5L5 efflux pump is threatening the drug regimens used to treat MDR-TB.

In our new preprint, we used structural and genetic approaches to better understand how MmpS5L5 effluxes bedaquiline and how future resistance may evolve. 🧵🔽

#TBsky #MicroSky #TB

(8/8) I am incredibly grateful to everyone who made this work possible
@medcambridge.bsky.social @mrclmb.bsky.social @cambiochem.bsky.social

Thanks to Lalita, Ben and Meindert for their guidance and support. Jan + Tanmay for their EM wizardry and all members of the Ramakrishnan/Luisi labs

#ENDTB

(7/8) Worryingly, we found variants in MmpL5 that increase bedaquiline resistance. These variants haven’t been seen clinically… so far

Bedaquiline is a drug the world cannot afford to lose

We hope this will prompt urgent development of efflux-avoiding BDQ derivatives and new efflux pump inhibitors

(5/8) @janboehning.bsky.social ‬ and @tbharat-lab.bsky.social did cryo-ET on Mtb. We found that the coiled-coil domain is only long enough to reach the Peptidoglycan-Arabinogalactan layer. A strongly conserved surface at the tip of MmpL5 hints at the presence of an elusive mycomembrane partner 🤔

Challenging times for biomedical research in the U.S. One of our grants was terminated and two others frozen. Thinking of colleagues from Bethesda to Boston to South Africa who are facing the same uncertainty. Now more than ever, we must speak up for the value of this work.

A New Type of Antifungal

Antifungal drug discovery gets an interesting and unexpected shot of good news:

Statement from WHO TB program on the impact of USAID cuts. TLDR: it's devastating.

hq_globaltuberculosisprogramme.cmail19.com/t/d-e-stuitu...

What's Happening Inside the NIH and NSF

A long post about what’s happening to the science funding agencies in the US and why. As mentioned, this one just kept getting longer even as I kept stripping curse words from it.

www.science.org/content/blog...

Lysenkoism was a Soviet-era pseudoscientific movement led by Trofim Lysenko, and endorsed by Stalin. It rejected established genetics science in favor of politically driven, unproven agricultural theories and ideological loyalty, leading to widespread crop failures and famine.

A timeline titled "The Golden Age of Antibiotics" shows when each antibiotic drug class was first available for medical use, with example antibiotics labeled. Classes are color-coded by their source: actinomycetes, other bacteria, fungi, or synthetic. Milestones include the first antibiotics (arsphenamines in 1910), as well as the discovery of many actinomycetes-derived antibiotics, such as streptomycin, and sulfonamides, penicillins, and tetracyclines. Data: Hutchings, Truman, Wilkinson (2019). Created by Saloni Dattani for Our World in Data.

Many people talk about the "Golden Age of Antibiotics", but I hadn't seen it visualized properly.

Just how many types of antibiotics were discovered during that time?

So, I visualized it myself!

Our first TB preprint with @jnb-lab.bsky.social is out! Using spectroscopic techniques from our lab, we resolve the exact mode of action of everyone's favourite TB drug, bedaquiline. I'd like to add a few comments about the microbiology part of the picture! #TBsky #MicroSky (1/7)

Finally we are able to share our story on the molecular mechanism of the transformative anti-tuberculosis drug bedaquiline within living cells

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

A (hopefully) broadly-accessible tutorial below ⬇️ (it ended up being really long!)

Chai-1 is released under an Apache 2.0 License, which means it can be used for both academic and commerical purposes, including for drug discovery.

Chai-1, the open source AF3 clone, is now available with an Apache 2 license github.com/chaidiscover...

We have quite a range of PhD projects this year, covering cryo-EM methods, bacteriology/bioenergetics, and infection/antibiotics/vaccines. Would really appreciate if people can RT and share with their teams!

Charles Darwin and Robert Koch walked into a bar... find out the outcome of this interaction here:

elifesciences.org/reviewed-pre...

Been thinking about creating a collection of good protein structure figures, as inspiration for my own work.

#1 www.nature.com/articles/s41...