Inhibition of Nonessential Bacterial Targets: Discovery of a Novel Serine O-Acetyltransferase Inhibitor

Joana Magalhães; Nina Franko; Samanta Raboni; Giannamaria Annunziato; Päivi Tammela; Agostino Bruno; Stefano Bettati; Andrea Mozzarelli; Marco Pieroni; Barbara Campanini; Gabriele Costantino

doi:10.1021/acsmedchemlett.9b00627

Inhibition of Nonessential Bacterial Targets: Discovery of a Novel Serine O-Acetyltransferase Inhibitor

ACS Med Chem Lett. 2020 Feb 13;11(5):790-797. doi: 10.1021/acsmedchemlett.9b00627. eCollection 2020 May 14.

Authors

Joana Magalhães¹, Nina Franko¹, Samanta Raboni^{1

2}, Giannamaria Annunziato¹, Päivi Tammela³, Agostino Bruno¹, Stefano Bettati^{4

5

2}, Andrea Mozzarelli^{1

5

2}, Marco Pieroni^{1

6}, Barbara Campanini¹, Gabriele Costantino^{1

6

7}

Affiliations

¹ P4T group and Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, 43124 Parma, Italy.
² Institute of Biophysics, CNR, 56124 Pisa, Italy.
³ Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), Helsinki FI-00014, Finland.
⁴ Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy.
⁵ National Institute of Biostructures and Biosystems, 00136 Rome, Italy.
⁶ Centro Interdipartimentale "Biopharmanet-tec", Università degli Studi di Parma, 43124 Parma, Italy.
⁷ Centro Interdipartimentale Misure (CIM) 'G. Casnati', University of Parma, 43124 Parma, Italy.

Abstract

In ϒ-proteobacteria and Actinomycetales, cysteine biosynthetic enzymes are indispensable during persistence and become dispensable during growth or acute infection. The biosynthetic machinery required to convert inorganic sulfur into cysteine is absent in mammals; therefore, it is a suitable drug target. We searched for inhibitors of Salmonella serine acetyltransferase (SAT), the enzyme that catalyzes the rate-limiting step of l-cysteine biosynthesis. The virtual screening of three ChemDiv focused libraries containing 91 243 compounds was performed to identify potential SAT inhibitors. Scaffold similarity and the analysis of the overall physicochemical properties allowed the selection of 73 compounds that were purchased and evaluated on the recombinant enzyme. Six compounds displaying an IC₅₀ <100 μM were identified via an indirect assay using Ellman's reagent and then tested on a Gram-negative model organism, with one of them being able to interfere with bacterial growth via SAT inhibition.