Identification and Biochemical Characterization of Pyrrolidinediones as Novel Inhibitors of the Bacterial Enzyme MurA.
Reem K Fathalla, Wolfgang Fröhner, Chantal D Bader, Patrick D Fischer, Charlotte Dahlem, Deep Chatterjee, Sebastian Mathea, Alexandra K Kiemer, Haribabu Arthanari, Rolf Müller, Mohammad Abdel-Halim, Christian Ducho, Matthias Engel
Author Information
Reem K Fathalla: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
Wolfgang Fröhner: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
Chantal D Bader: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany.
Patrick D Fischer: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
Charlotte Dahlem: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
Deep Chatterjee: Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt/Main, Germany.
Sebastian Mathea: Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt/Main, Germany.
Alexandra K Kiemer: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany. ORCID
Haribabu Arthanari: Department of Cancer Biology, Dana-Farber Cancer Institute, 02215 Boston, Massachusetts, United States.
Rolf Müller: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany.
Mohammad Abdel-Halim: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. ORCID
Christian Ducho: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany. ORCID
Matthias Engel: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany. ORCID
To develop novel antibiotics, targeting the early steps of cell wall peptidoglycan biosynthesis seems to be a promising strategy that is still underutilized. MurA, the first enzyme in this pathway, is targeted by the clinically used irreversible inhibitor fosfomycin. However, mutations in its binding site can cause bacterial resistance. We herein report a series of novel reversible pyrrolidinedione-based MurA inhibitors that equally inhibit wild type (WT) MurA and the fosfomycin-resistant MurA C115D mutant, showing an additive effect with fosfomycin for the inhibition of WT MurA. For the most potent inhibitor (IC = 4.5 μM), the mode of inhibition was analyzed using native mass spectrometry and protein NMR spectroscopy. The compound class was nontoxic against human cells and highly stable in human S9 fraction, human plasma, and bacterial cell lysate. Taken together, this novel compound class might be further developed toward antibiotic drug candidates that inhibit cell wall synthesis.
References
J Med Chem. 2014 Sep 25;57(18):7590-9
[PMID: 25148591]
Chemistry. 2014 Nov 17;20(47):15292-7
[PMID: 25318977]
Biochemistry. 1997 Mar 18;36(11):3050-5
[PMID: 9115979]
Stud Mycol. 2011 Jun 30;69(1):57-80
[PMID: 21892243]
