My first preprint calls for my first tweet thread! A joint effort between @MarwaMikati and I with help and support from many others in the @odomjohnlab, @Muller_Lab, Dowd lab, and others summarized below. https://biorxiv.org/content/10.1101/2020.07.23.214460v1….
Antimicrobial prodrug activation by the staphylococcal glyoxalase GloB
With the rising prevalence of multidrug-resistance, there is an urgent need to develop novel antibiotics. Many putative antibiotics demonstrate promising in vitro potency but fail in vivo due to poor...https://biorxiv.org/content/10.1101/2020.07.23.214460v1
1) 1)Pro-drugging strategies have a lot of potential impact in antimicrobial development. We can use them to modify whether drugs get absorbed, where they go, and whether or not they are metabolized. They can even be deployed to get your drug across those greasy membranes!
2) While it would be wonderful to have a magic, get-your-drug-into-the-microbe-of-interest-moiety, we don't yet have that. Current chemical strategies are cleaved by serum esterases (curses!). Maybe, if we understand how microbes activate their prodrugs, we could hijack those
2 cont) mechanisms and develop microbe specific prodrugs. This could also help us reduce unforseen drug toxicity (the drug that isn't active on human cells can't be toxic to them).
3) Using zoonotic staphylococci as a tool, we evolve resistance specifically to the prodrugged version of the isoprenoid biosynthesis inhibitor POM-ERJ. Our resistant mutants are cross resistant to other drugs using the same prodrugging strategy -> resistance is prodrug-specific
4) Whole genome sequencing tells us that our prodrug resistant zoonotic staphylococci (S. schleiferi and S. pseudintermedius) are enriched in mutations in the enzyme "GloB" a hydroxyacylglutathione hydrolase. Several mutations in the predicted active site of GloB.
5) Recombinant GloB is sufficient to activate our lipophilic prodrugs! We can also feed POM-ERJ to our resistant staphylococci (with GloB mutations) and find that the resistant mutants never make active drug (but wild-type staphylococci do).
6) There is substantial sequence variation in GloB orthologs across the microbial world. There are also big differences in the active site structure of Human GloB and the predicted structures of GloB from our zoonotic staphylococci.
Can we use GloB to design microbe specific prodrugs? Would GloB-targeted prodrugs be specific to bacterial taxa? Stay tuned!