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.
Highlights
Cystic fibrosis (CF) is a rare inherited disease, caused by the malfunction of the chloride channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR)
One group of bacteria that causes life-threatening infections in CF people belongs to the Burkholderia cepacia complex (Bcc), and is responsible for the “Cepacia Syndrome” which leads to a rapid deterioration of lung function and affects the life expectancy of CF patients [5]
We focused on GR from B. cenocepacia J2315 (BcGR), and we performed library screening for the identification of compounds targeting the recombinant enzyme in vitro
Summary
Cystic fibrosis (CF) is a rare inherited disease, caused by the malfunction of the chloride channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Persistent lung infections are responsible for irreversible bronchiectasis and respiratory failure, and represent the main cause of morbidity and mortality in CF individuals [1,2,3,4]. One group of bacteria that causes life-threatening infections in CF people belongs to the Burkholderia cepacia complex (Bcc), and is responsible for the “Cepacia Syndrome” which leads to a rapid deterioration of lung function and affects the life expectancy of CF patients [5]. The treatment of patients with Bcc is difficult because of flexible genome structure and diverse metabolic activity: bacteria can produce a wide variety of potential virulence factors and exhibit innate or acquired resistance to many commonly used antibiotics and disinfectants. The complex is resistant to a PLOS ONE | DOI:10.1371/journal.pone.0167350. The complex is resistant to a PLOS ONE | DOI:10.1371/journal.pone.0167350 November 29, 2016
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