INVESTIGADORES
KLINKE Sebastian
congresos y reuniones científicas
Título:
Identification of antimicrobial compounds against brucellosis targetiing riboflavin synthase (Póster)
Autor/es:
MARIELA DEL C. CARRICA; MARÍA I. SERER; MARÍA L. CERUTTI; JOERG TRAPPE; SANDRA LÓPEZ ROMERO; HERNÁN R. BONOMI; SEBASTIÁN KLINKE; FERNANDO A. GOLDBAUM
Lugar:
Buenos Aires
Reunión:
Congreso; Reunión Conjunta de Sociedades de Biociencias 2017; 2017
Institución organizadora:
SAIC, SAIB, SAI, SAA, SAB, SAB, SAFE, SAFIS, SAH y SAP
Resumen:
Brucellaspp. are facultative intracellular bacteria, that are adapted to life withincells of a large variety of mammals. These bacteria are the causative agent ofbrucellosis, a zoonotic infection with the highest incidence in the worldaffecting livestock and humans and for which a safe and completely reliablevaccine is still unavailable. Riboflavin (vitamin B2) is the universal precursorfor the biosynthesis of FMN and FAD, two versatile redox cofactors in nature.This vitamin is biosynthesized in microorganisms and plants but must be obtainedfrom dietary sources by animals. Owing to the absence of this pathway inanimals and humans and the fact that endogenous riboflavin synthesis isnecessary for the growth of many pathogens, this pathway is regarded as a richresource of targets for the development of new antimicrobial agents. In thiswork, we describe a High-Throughput Screening (HTS) approach for theidentification of inhibitors of the enzymatic activity of Riboflavin Synthase,the last enzyme of the riboflavin biosynthesis pathway, along with itssubsequent validation as potential drugs candidates in an in vitro model forbrucellosis infection. From a set of 44,000 highly diverse low-molecular weightcompounds, a total of 163 exhibited a 30% threshold inhibition at 30 microMconcentration. Further secondary screening with dose-response curves allowedfor the identification of ten molecules with 50% inhibitory concentrations(IC50s) in the low micromolar range. Interestingly, a subset of five compoundssharing a 2-Phenylamidazo[2,1-b][1,3]benzothiazole chemical scaffold alsodisplayed bactericide activity against B. abortus. Furthermore, we tested the effectof the two most promising compounds on the survival of intracelular bacteriaand we found that they are able to inhibit Brucella growth in a murinemacrophage cell line. These findings represent a promissory advancement in thepursuit of antimicrobial compounds against brucellosis.