Identification and characterization of an anti-pseudomonal dichlorocarbazol derivative displaying anti-biofilm activity

Liebens, Veerle; Gerits, Evelien; Knapen, Wouter; Swings, Toon; Beullens, Serge; Steenackers, Hans; Robijns, Stijn; Lippell, Anna; O’Neill, Alex J.; Veber, Matija; Fröhlich, Mirjam; Krona, Annika; Lövenklev, Maria; Corbau, Romuald; Marchand, Arnaud; Chaltin, Patrick; Brucker, Klaas De; Thevissen, Karin; Cammue, Bruno P. A.; Fauvart, Maarten; Verstraeten, Natalie; Michiels, Jan

doi:10.1016/j.bmcl.2014.10.039

Cited by 17 publications

(19 citation statements)

References 39 publications

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“…A small-molecule library comprising 23,909 diverse molecules (23) was screened to identify compounds that reduce the persister fraction of P. aeruginosa when they are used in combination with the fluoroquinolone antibiotic ofloxacin (10 g/ml). To confirm the antipersister activity of the identified compounds, a range of concentrations (0 to 200 M) was tested and the efficacy was assessed through viable cell counting.…”

Section: Resultsmentioning

confidence: 99%

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Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Liebens

Defraine

Knapen

et al. 2017

Antimicrob Agents Chemother

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Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current 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, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a smallmolecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 10 6 -fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. 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.

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Section: Resultsmentioning

confidence: 99%

“…Concentrations are indicated throughout the text. The small-molecule library was provided by the Centre for Drug Design and Discovery (CD3) of KU Leuven (23,53). The bacterial strains used in this study are listed in Table 2.…”

Section: Methodsmentioning

confidence: 99%

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Liebens

Defraine

Knapen

et al. 2017

Antimicrob Agents Chemother

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“…Recently, we identified a N‐alkylated 3, 6‐dihalogenocarbazol 1‐(sec‐butylamino)‐3‐(3,6‐dichloro‐9H‐carbazol‐9‐yl)propan‐2‐ol as an antibacterial compound. This compound, SPI031, exhibits broad‐spectrum antibacterial activity against Gram‐positive and Gram‐negative pathogens, including S. aureus and P. aeruginosa . In the present study, we investigated the potential of SPI031 for use as a passive implant coating.…”

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confidence: 99%

Antibacterial activity of a new broad‐spectrum antibiotic covalently bound to titanium surfaces

Gerits

Kucharíková

Dijck

et al. 2016

Journal Orthopaedic Research

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Biofilm-associated infections, particularly those caused by Staphylococcus aureus, are a major cause of implant failure. Covalent coupling of broad-spectrum antimicrobials to implants is a promising approach to reduce the risk of infections. In this study, we developed titanium substrates on which the recently discovered antibacterial agent SPI031, a N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol, was covalently linked (SPI031-Ti). We found that SPI031-Ti substrates prevent biofilm formation of S. aureus and Pseudomonas aeruginosa in vitro, as quantified by plate counting and fluorescence microscopy. To test the effectiveness of SPI031-Ti substrates in vivo, we used an adapted in vivo biomaterial-associated infection model in mice in which SPI031-Ti substrates were implanted subcutaneously and subsequently inoculated with S. aureus. Using this model, we found a significant reduction in biofilm formation (up to 98%) on SPI031-Ti substrates compared to control substrates. Finally, we demonstrated that the functionalization of the titanium surfaces with SPI031 did not influence the adhesion and proliferation of human cells important for osseointegration and bone repair. In conclusion, these data demonstrate the clinical potential of SPI031 to be used as an antibacterial coating for implants, thereby reducing the incidence of implant-associated infections. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2191-2198, 2016.

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“…We screened a compound library in search for new molecules that exhibit activity against the opportunistic pathogen Pseudomonas aeruginosa [114]. From this screening, a dichlorocarbazol derivative was identified as a new antibacterial agent with broad-spectrum activity, including activity against P. gingivalis biofilms.…”

Section: Treatment Of P Gingivalis–related Infectionsmentioning

confidence: 99%

New approaches to combat Porphyromonas gingivalis biofilms

Gerits

Verstraeten

Michiels

2017

Journal of Oral Microbiology

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In nature, bacteria predominantly reside in structured, surface-attached communities embedded in a self-produced, extracellular matrix. These so-called biofilms play an important role in the development and pathogenesis of many infections, as they are difficult to eradicate due to their resistance to antimicrobials and host defense mechanisms. This review focusses on the biofilm-forming periodontal bacterium Porphyromonas gingivalis. Current knowledge on the virulence mechanisms underlying P. gingivalis biofilm formation is presented. In addition, oral infectious diseases in which P. gingivalis plays a key role are described, and an overview of conventional and new therapies for combating P. gingivalis biofilms is given. More insight into this intriguing pathogen might direct the development of better strategies to combat oral infections.

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Identification and characterization of an anti-pseudomonal dichlorocarbazol derivative displaying anti-biofilm activity

Cited by 17 publications

References 39 publications

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Antibacterial activity of a new broad‐spectrum antibiotic covalently bound to titanium surfaces

New approaches to combat Porphyromonas gingivalis biofilms

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