title: Dictyostelium discoideum as a surrogate host-microbe model for antivirulence screening in Pseudomonas aeruginosa PAO1.
abstract: The interest of the pharmaceutical industry in developing new antibiotics is decreasing, as established screening systems which identify compounds that kill or inhibit the growth of bacteria can no longer be used. Consequently, antimicrobial screening using classical minimum inhibitory concentration (MIC) measurements is becoming obsolete. The discovery of antimicrobial agents that specifically target a bacterial pathogen without affecting the host and its beneficial bacteria is a promising strategy. However, few host-microbe models are available for in vivo screening of novel antivirulence molecules. Here we designed high-throughput developmental assays in the social amoeba Dictyostelium discoideum to measure Pseudomonas aeruginosa virulence and to screen for novel antivirulence molecules without side effects to the host and its beneficial bacteria Klebsiella aerogenes. Thirty compounds were evaluated that had been previously selected by virtual screening for inhibitors of P. aeruginosa PAO1 polyphosphate kinase 1 (PaPPK1) and diverse compounds with combined PPK1 inhibitory and antivirulence activities were identified. This approach demonstrates that D. discoideum is a suitable surrogate host for preliminary high-throughput screening of antivirulence agents and that PPK1 is a suitable target for developing novel antivirulence compounds that can be further validated in mammalian models.
authors.affiliation: Systems Microbiology Laboratory, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Bravo-Toncio
authors.affiliation: Systems Microbiology Laboratory, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Javiera A
authors.initials: JA
authors.lastname: Álvarez
authors.affiliation: Systems Microbiology Laboratory, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Francisca
authors.initials: F
authors.lastname: Campos
authors.affiliation: Systems Microbiology Laboratory, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Javiera
authors.initials: J
authors.lastname: Ortíz-Severín
authors.affiliation: Systems Microbiology Laboratory, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Varas
authors.affiliation: Laboratorio de Bioquímica, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cabrera
authors.affiliation: Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Facultad de Ciencia, Universidad San Sebastián, Santiago, Chile.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.affiliation: Systems Microbiology Laboratory, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. Electronic address: fpchavez@uchile.cl.
authors.forename: Francisco P
authors.initials: FP
authors.lastname: Chávez
mesh_terms: D000890:Anti-Infective Agents / Q000302:isolation & purification* / Q000494:pharmacology; D004023:Dictyostelium / Q000382:microbiology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays; D008962:Models, Theoretical; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D014774:Virulence / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents
keywords: Antivirulence; Host–pathogen interaction; In silico drug discovery; Polyphosphate; Social amoeba