Annunziato G(1), Spadini C(2), Franko N(3), Storici P(4), Demitri N(4), Pieroni M(1), Flisi S(2), Rosati L(2), Iannarelli M(2), Marchetti M(5), Magalhaes J(1), Bettati S(6)(5)(7), Mozzarelli A(3)(5)(7), Cabassi CS(2), Campanini B(3)(5), Costantino G(1). Author information:
(1)P4T Group, Department of Food and Drugs, University of Parma, Parco Area
delle Scienze 27/A, 43124 Parma, Italy.
(2)Operative Unit of Animals Infectious Diseases, Department of Veterinary
Science, University of Parma, via del Taglio, 8, 43126 Parma, Italy.
(3)Laboratory of Biochemistry and Molecular Biology, Department of Food and
Drugs, University of Parma, via Parco Area delle Scienze 23/A, 43124 Parma,
(4)Elettra - Sincrotrone Trieste S.C.p.A., SS 14 - km 163,5 in AREA Science
Park, 34149 Trieste, Italy.
(5)Biopharmanet-TEC Interdepartmental Center, University of Parma, 43124 Parma,
(6)Department of Medicine and Surgery, University of Parma, via Volturno, 39,
43125 Parma, Italy.
(7)Institute of Biophysics, CNR, 56124 Pisa, Italy.
Antibacterial adjuvants are of great significance, since they allow the therapeutic dose of conventional antibiotics to be lowered and reduce the insurgence of antibiotic resistance. Herein, we report that an O-acetylserine sulfhydrylase (OASS) inhibitor can be used as a colistin adjuvant to treat infections caused by Gram-positive and Gram-negative pathogens. A compound that binds OASS with a nM dissociation constant was tested as an adjuvant of colistin against six critical pathogens responsible for infections spreading worldwide, Escherichia coli, Salmonella enterica serovar Typhimurium, Klebisiella pneumoniae, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Staphylococcus pseudintermedius. The compound showed promising synergistic or additive activities against all of them. Knockout experiments confirmed the intracellular target engagement supporting the proposed mechanism of action. Moreover, compound toxicity was evaluated by means of its hemolytic activity against sheep defibrinated blood cells, showing a good safety profile. The 3D structure of the compound in complex with OASS was determined at 1.2 Å resolution by macromolecular crystallography, providing for the first time structural insights about the nature of the interaction between the enzyme and this class of competitive inhibitors. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants and the structural basis for further structure-activity relationship studies.
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