A series of new N, N'-diarylurea derivatives were designed and synthesized, some of which exhibited potent antibacterial activity against the drug-susceptible and drug-resistant Gram-positive strains. Especially, compounds 2c, 2g-2l showed broader antibacterial spectrum and more potent antibacterial activity (MIC = 0.30-2.72 μM) against MRSA and MRSE than the control levofloxacin (MIC = 0.69-22.14 μM). In addition, compounds 2c, 2g, 2h and 2l exhibited much better antibacterial activity (MIC = 1.29-2.86 μM) against VRE (E. faecium) than sorafenib (MIC = 275.37 μM), PK150 (MIC = 5.07-10.13 μM) and SC78 (MIC = 2.40-4.79 μM). More importantly, the low cytotoxicity of compounds on cell lines HeLa and HepG2 implied a relatively wide therapeutic window, which was of high importance for further study.

03 Aug 2020·Applied and Environmental MicrobiologyQ2 · BIOLOGY

Comparative Target Analysis of Chlorinated Biphenyl Antimicrobials Highlights MenG as a Molecular Target of Triclocarban

Q2 · BIOLOGY

Article

Author: Layer, Franziska ; Bender, Jennifer ; Mostert, Dietrich ; Hackl, Mathias W. ; Macsics, Robert ; Sieber, Stephan A. ; Fetzer, Christian

TCC’s widespread use as an antimicrobial agent has made it a ubiquitous environmental pollutant despite its withdrawal due to ecological and toxicological concerns. With its antibacterial mechanism of action still being unknown, we undertook a comparative target analysis between TCC, PK150 (a recently discovered antibacterial compound with structural resemblance to TCC), and TCS (another widely employed chlorinated biphenyl antimicrobial) in the bacterium Staphylococcus aureus . We show that there are distinct differences in each compound’s mode of action, but also identify a shared target between TCC and PK150, the interference with menaquinone metabolism by inhibition of MenG. The prevailing differences, however, which also manifest in a remarkably better broad-spectrum activity of PK150, suggest that even high levels of TCC or TCS resistance observed by continuous environmental exposure may not affect the potential of PK150 or related N , N′ -diaryl urea compounds as new antibiotic drug candidates against multidrug-resistant infections.

01 Feb 2020·Nature ChemistryQ1 · CHEMISTRY

Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Q1 · CHEMISTRY

Article

Author: Rohde, Manfred ; Hacker, Stephan M ; Chaves-Moreno, Diego ; Ugur, Ilke ; Wuest, William M ; Fetzer, Christian ; Rox, Katharina ; Jennings, Megan C ; Antes, Iris ; Pieper, Dietmar H ; Lehmann, Johannes ; Korotkov, Vadim S ; Medina, Eva ; Mandl, Franziska A M ; Sieber, Stephan A ; Kunold, Elena ; Hackl, Mathias W ; Reinecke, Maria ; Le, Philipp ; Kuster, Bernhard ; Macsics, Robert

New drugs are desperately needed to combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we report screening commercial kinase inhibitors for antibacterial activity and found the anticancer drug sorafenib as major hit that effectively kills MRSA strains. Varying the key structural features led to the identification of a potent analogue, PK150, that showed antibacterial activity against several pathogenic strains at submicromolar concentrations. Furthermore, this antibiotic eliminated challenging persisters as well as established biofilms. PK150 holds promising therapeutic potential as it did not induce in vitro resistance, and shows oral bioavailability and in vivo efficacy. Analysis of the mode of action using chemical proteomics revealed several targets, which included interference with menaquinone biosynthesis by inhibiting demethylmenaquinone methyltransferase and the stimulation of protein secretion by altering the activity of signal peptidase IB. Reduced endogenous menaquinone levels along with enhanced levels of extracellular proteins of PK150-treated bacteria support this target hypothesis. The associated antibiotic effects, especially the lack of resistance development, probably stem from the compound's polypharmacology.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Positive Bacterial Infections	Preclinical	United States	Emory University	14 Mar 2025

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