Here’s a new wrinkle.  Our antibiotics are compounds that interfere with bacterial cell wall production, membrane integrity, protein biosynthesis, and DNA synthesis.  But, given our overuse (and incomplete drug regimens), the microbes we hope to kill have already developed resistance to the antibiotics in our arsenal.

And, we haven’t really found a bunch of new antibiotics to replenish our arsenal.  Which is why a multi-center, multidisciplinary group (primarily in Germany) screened commercially available kinase inhibitors for antimicrobial capabilities.

Why kinase inhibitors? After all, kinase inhibitors are known to block the growth of new blood vessels and prevent some cancer cells from growing.  But, this group wasn’t seeking out new anti-cancer therapies.

No, they were using another piece of logic.  We know that kinases provide critical functionality to cells- regulating transcription, cell cycle regulation, metabolic activities, virulence, and drug resistance in microbes.  In particular, these pathways are important ways to terminate the growth and viability of methicillin resistant Staphylococcus aureus (MRSA), antibiotic resistant tuberculosis, and other recalcitrant microbes.  (ß-lactam antibiotics have no effect on MRSA.)

So, these researchers from the Technical University of Munich (Drs. SA Sieber [primary author], P Le, E Kunold, R Macsis, I Ugur, M Reinecke, MW Hackl, C Fetzer, FA Mandl, J Lehmann, VS Korotokov, SM Hacker, B Kuster, and  I Antes), the Helmholtz Center for Infection Research [Braunschweig] (Dr. Sieber also has an appointment here, as well as Drs. K Rox, D Chaves-Moreno, DH Pieper, M Rohde, and E Medina), plus Dr. MC Jennings (Temple, Philadelphia), and Dr. WM Wuest (Emory, Atlanta) performed these screening tests and found one anticancer drug to be effective against the recalcitrant microbes.  The title of their publication in Nature Chemistry is Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters, and biofilms.  (The title is most descriptive!)

The candidate they chose was the anticancer drug, sorafenib; research had indicated that it had some effectiveness against MRSA.  (It wasn’t totally clear than sorafenib was actually a kinase; but it really is.) So, the research team modified its structure, creating a variety of different analogs.  But, the one they call PK150 had at least a decade more effectivity against MRSA.   It was most effective at very low concentrations not just to MRSA, but to biofilms (80% reduction in size over 24 hours) and other microbial persisters (such as vancomycin resistant enterococci, aka VRE)- without inducing an in vitro resistance.  (PK150  demonstrated in vivo efficacy and manifested oral bioavailability.)  The tests were effected in mice with bloodstream infections.

(Here comes some technical info.  Feel free to skip over it. Conventional antibiotics (penicillin, methicillin) interfere with cell wall formation.   PK150 interfered with menaquinone biosynthesis [demethymenaquinone methyltransferase inhibition, vital for microbial respiration and energy metabolism] and increases protein secretion out of the cells [change in signal peptidase IB activity, controlling the cell wall thickness; which allows the cells to burst].  PK150 no longer binds to human kinases (as did the sorafenib originally)- instead it targets the microbes directly.)

Compared to the standard, levofloxacin, PK150 matched its potency, with better bioavailability.  No resistance to PK150 was manifested in the lab-grown microbes, as opposed to ofloxacin and sorafenib, which did.   Most importantly, PK150 can be made into an orally-administered tablet and remains stable for several hours within the human body.

Now, this IS good news for the world.

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