EXPERIMENTAL THERAPEUTICScrossmIdentification of 1-((two,4Dichlorophenethyl)Amino)-3Phenoxypropan-2-ol
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EXPERIMENTAL THERAPEUTICScrossmIdentification of 1-((two,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 Style and Discovery, Research and Improvement, KU Leuven, Leuven, Belgiumc; imec, Department of Life Sciences and Imaging, Clever Electronics Unit, Leuven, BelgiumdAntibiotics typically fail to fully eradicate a bacterial population, leaving a little fraction of transiently antibiotic-tolerant persister cells intact. Persisters are hence observed to become a significant cause of treatment failure and greatly contribute for the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging for the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, as a result of growing resistance against most traditional antibiotics, posing a critical threat to human overall health. Significantly contributing for the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of those cells would therefore considerably enhance patient outcomes.Androgen receptor Protein site In this study, a smallmolecule library was screened for compounds that, in mixture with all the fluoroquinolone antibiotic ofloxacin, decreased the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Depending on the early structure-activity partnership, 1-((two,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for additional characterization. Mixture 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. Additional characterization on the compound revealed a direct and efficient killing of persister cells.CD5L, Human (HEK293, His) SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity.PMID:24101108 In conclusion, we identified a novel antipersister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.ABSTRACT Keyword phrases Pseudomonas aeruginosa, antibiotic tolerance, mixture therapy, antipersister therapiesReceived 20 April 2017 Returned for modification five June 2017 Accepted 9 June 2017 Accepted manuscript posted on the net 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-((2,4dichlorophenethyl)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 very first authors. M.F. and J.M. contributed equally to this article as senior authors.
