Bavirin. Even

EXPERIMENTAL THERAPEUTICScrossmIdentification of 1-((two,4Dichlorophenethyl)Amino)-3Phenoxypropan-2-ol
Bavirin. Even
EXPERIMENTAL THERAPEUTICScrossmIdentification of 1-((2,4Dichlorophenethyl)Amino)-3Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosaVeerle Liebens,a Valerie Defraine,a Wouter Knapen,a Toon Swings,a Serge Beullens,a Romu Corbau,b* Arnaud Marchand,b Patrick Chaltin,b,c Maarten Fauvart,a,d Jan MichielsaCentre of Microbial and Plant Genetics, KU Leuven, Leuven, Belgiuma; CISTIM Leuven vzw, Leuven, Belgiumb; Centre for Drug Design and style and Discovery, Research and Development, KU Leuven, Leuven, Belgiumc; imec, Department of Life Sciences and Imaging, Wise Electronics Unit, Leuven, BelgiumdAntibiotics generally fail to absolutely eradicate a bacterial population, leaving a modest fraction of transiently antibiotic-tolerant persister cells intact. Persisters are for that reason seen to be a major cause of treatment failure and greatly contribute for the recalcitrant nature of chronic infections. The existing study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, because of increasing resistance against most standard antibiotics, posing a really serious threat to human well being. Drastically contributing towards the challenging therapy of P. aeruginosa infections could be the presence of persister cells, and elimination of those cells would hence significantly improve patient outcomes. In this study, a smallmolecule library was screened for compounds that, in combination using the fluoroquinolone antibiotic ofloxacin, reduced the number of P.195387-29-2 web aeruginosa persisters compared to the number accomplished with therapy using the antibiotic alone. Depending on the early structure-activity partnership, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was chosen for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 106fold in each lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 brought on no erythrocyte harm and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against P.Buy1620575-06-5 aeruginosa with promising applications for the style of novel, case-specific combination therapies within the fight against chronic infections.PMID:23771862 ABSTRACT Search phrases Pseudomonas aeruginosa, antibiotic tolerance, mixture therapy, antipersister therapiesReceived 20 April 2017 Returned for modification 5 June 2017 Accepted 9 June 2017 Accepted manuscript posted on line 19 June 2017 Citation Liebens V, Defraine V, Knapen W, Swings T, Beullens S, Corbau R, Marchand A, Chaltin P, Fauvart M, Michiels J. 2017. Identification of 1-((two,4dichlorophenethyl)amino)-3-phenoxypropan2-ol, a novel antibacterial compound active against persisters of Pseudomonas aeruginosa. Antimicrob Agents Chemother 61:e00836-17. https://doi.org/10.1128/AAC.00836-17. Copyright 2017 American Society for Microbiology. All Rights Reserved. Address correspondence to Jan Michiels, [email protected].* Present address: Romu Corbau, Children’sHospital of Philadelphia, Philadelphia, Pennsylvania, USA. V.L. and V.D. contributed equally to this short article as 1st authors. M.F. and J.M. contributed equally to this short article as senior authors.