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Elucidation of the mode of action of a new antibacterial compound active against Staphylococcus aureus and Pseudomonas aeruginosa

Evelien Gerits, Eline Blommaert, Anna Lippell, Alex J O'Neill, Bram Weytjens, Dries De Maeyer, Ana Carolina Fierro, Kathleen Marchal UGent, Arnaud Marchand, Patrick Chaltin, et al. (2016) PLOS ONE. 11(5).
abstract
Nosocomial and community-acquired infections caused by multidrug resistant bacteria represent a major human health problem. Thus, there is an urgent need for the development of antibiotics with new modes of action. In this study, we investigated the antibacterial characteristics and mode of action of a new antimicrobial compound, SPI031 (N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl) propan-2-ol), which was previously identified in our group. This compound exhibits broad-spectrum antibacterial activity, including activity against the human pathogens Staphylococcus aureus and Pseudomonas aeruginosa. We found that SPI031 has rapid bactericidal activity (7-log reduction within 30 min at 4x MIC) and that the frequency of resistance development against SPI031 is low. To elucidate the mode of action of SPI031, we performed a macromolecular synthesis assay, which showed that SPI031 causes non-specific inhibition of macromolecular biosynthesis pathways. Liposome leakage and membrane permeability studies revealed that SPI031 rapidly exerts membrane damage, which is likely the primary cause of its antibacterial activity. These findings were supported by a mutational analysis of SPI031-resistant mutants, a transcriptome analysis and the identification of transposon mutants with altered sensitivity to the compound. In conclusion, our results show that SPI031 exerts its antimicrobial activity by causing membrane damage, making it an interesting starting point for the development of new antibacterial therapies.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
IBCN, DAPTOMYCIN, ANTIBIOTICS, RESISTANCE, INFECTIONS, MEMBRANE, HIGH-INOCULUM, BACTERICIDAL ACTIVITY, PHARMACODYNAMIC MODEL, ESCHERICHIA-COLI, MYCOBACTERIUM-TUBERCULOSIS
journal title
PLOS ONE
PLoS One
volume
11
issue
5
article number
e0155139
pages
17 pages
Web of Science type
Article
Web of Science id
000376587300033
JCR category
MULTIDISCIPLINARY SCIENCES
JCR impact factor
2.806 (2016)
JCR rank
15/64 (2016)
JCR quartile
1 (2016)
ISSN
1932-6203
DOI
10.1371/journal.pone.0155139
project
Bioinformatics: from nucleotids to networks (N2N)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
7775178
handle
http://hdl.handle.net/1854/LU-7775178
date created
2016-06-27 13:33:06
date last changed
2017-04-25 07:26:46
@article{7775178,
  abstract     = {Nosocomial and community-acquired infections caused by multidrug resistant bacteria represent a major human health problem. Thus, there is an urgent need for the development of antibiotics with new modes of action. In this study, we investigated the antibacterial characteristics and mode of action of a new antimicrobial compound, SPI031 (N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl) propan-2-ol), which was previously identified in our group. This compound exhibits broad-spectrum antibacterial activity, including activity against the human pathogens Staphylococcus aureus and Pseudomonas aeruginosa. We found that SPI031 has rapid bactericidal activity (7-log reduction within 30 min at 4x MIC) and that the frequency of resistance development against SPI031 is low. To elucidate the mode of action of SPI031, we performed a macromolecular synthesis assay, which showed that SPI031 causes non-specific inhibition of macromolecular biosynthesis pathways. Liposome leakage and membrane permeability studies revealed that SPI031 rapidly exerts membrane damage, which is likely the primary cause of its antibacterial activity. These findings were supported by a mutational analysis of SPI031-resistant mutants, a transcriptome analysis and the identification of transposon mutants with altered sensitivity to the compound. In conclusion, our results show that SPI031 exerts its antimicrobial activity by causing membrane damage, making it an interesting starting point for the development of new antibacterial therapies.},
  articleno    = {e0155139},
  author       = {Gerits, Evelien and Blommaert, Eline and Lippell, Anna and O'Neill, Alex J and Weytjens, Bram and De Maeyer, Dries and Fierro, Ana Carolina and Marchal, Kathleen and Marchand, Arnaud and Chaltin, Patrick and Spincemaille, Pieter and De Brucker, Katrijn and Thevissen, Karin and Cammue, Bruno PA and Swings, Toon and Liebens, Veerle and Fauvart, Maarten and Verstraeten, Natalie and Michiels, Jan},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keyword      = {IBCN,DAPTOMYCIN,ANTIBIOTICS,RESISTANCE,INFECTIONS,MEMBRANE,HIGH-INOCULUM,BACTERICIDAL ACTIVITY,PHARMACODYNAMIC MODEL,ESCHERICHIA-COLI,MYCOBACTERIUM-TUBERCULOSIS},
  language     = {eng},
  number       = {5},
  pages        = {17},
  title        = {Elucidation of the mode of action of a new antibacterial compound active against Staphylococcus aureus and Pseudomonas aeruginosa},
  url          = {http://dx.doi.org/10.1371/journal.pone.0155139},
  volume       = {11},
  year         = {2016},
}

Chicago
Gerits, Evelien, Eline Blommaert, Anna Lippell, Alex J O’Neill, Bram Weytjens, Dries De Maeyer, Ana Carolina Fierro, et al. 2016. “Elucidation of the Mode of Action of a New Antibacterial Compound Active Against Staphylococcus Aureus and Pseudomonas Aeruginosa.” Plos One 11 (5).
APA
Gerits, E., Blommaert, E., Lippell, A., O’Neill, A. J., Weytjens, B., De Maeyer, D., Fierro, A. C., et al. (2016). Elucidation of the mode of action of a new antibacterial compound active against Staphylococcus aureus and Pseudomonas aeruginosa. PLOS ONE, 11(5).
Vancouver
1.
Gerits E, Blommaert E, Lippell A, O’Neill AJ, Weytjens B, De Maeyer D, et al. Elucidation of the mode of action of a new antibacterial compound active against Staphylococcus aureus and Pseudomonas aeruginosa. PLOS ONE. 2016;11(5).
MLA
Gerits, Evelien, Eline Blommaert, Anna Lippell, et al. “Elucidation of the Mode of Action of a New Antibacterial Compound Active Against Staphylococcus Aureus and Pseudomonas Aeruginosa.” PLOS ONE 11.5 (2016): n. pag. Print.