title: Biochemical Characterization of Glutamate Racemase-A New Candidate Drug Target against Burkholderia cenocepacia Infections.
abstract: The greatest obstacle for the treatment of cystic fibrosis patients infected with the Burkholderia species is their intrinsic antibiotic resistance. For this reason, there is a need to develop new effective compounds. Glutamate racemase, an essential enzyme for the biosynthesis of the bacterial cell wall, is an excellent candidate target for the design of new antibacterial drugs. To this aim, we recombinantly produced and characterized glutamate racemase from Burkholderia cenocepacia J2315. From the screening of an in-house library of compounds, two Zn (II) and Mn (III) 1,3,5-triazapentadienate complexes were found to efficiently inhibit the glutamate racemase activity with IC50 values of 35.3 and 10.0 μM, respectively. Using multiple biochemical approaches, the metal complexes have been shown to affect the enzyme activity by binding to the enzyme-substrate complex and promoting the formation of an inhibited dimeric form of the enzyme. Our results corroborate the value of glutamate racemase as a good target for the development of novel inhibitors against Burkholderia.
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.|Department of Microbiology, Baku State University, Baku, Azerbaijan.
authors.forename: Aygun
authors.initials: A
authors.lastname: Israyilova
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buroni
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Forneris
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.
authors.forename: Viola Camilla
authors.initials: VC
authors.lastname: Scoffone
authors.affiliation: Department of Organic Chemistry, Baku State University, Baku, Azerbaijan.
authors.forename: Namiq Q
authors.initials: NQ
authors.lastname: Shixaliyev
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Riccardi
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, Pavia, Italy.
authors.forename: Laurent Roberto
authors.identifier: http://orcid.org/0000-0003-0348-9764
authors.initials: LR
authors.lastname: Chiarelli
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019121:Burkholderia Infections / Q000382:microbiology; D057508:Burkholderia cenocepacia / Q000187:drug effects / Q000201:enzymology* / Q000302:isolation & purification; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008345:Manganese / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D055550:Protein Stability; D015032:Zinc / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D008345:Manganese; D000591:Amino Acid Isomerases; C062292:glutamate racemase; D015032:Zinc