Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli.
Background Enteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to dealing with persistent infection by these exceptional colonizers, which form copious biofilms....
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ftdoajarticles:oai:doaj.org/article:3cf047e0937c420ea77f476bc3e3709b 2023-05-15T15:12:23+02:00 Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. David A Kwasi Chinedum P Babalola Olujide O Olubiyi Jennifer Hoffmann Ikemefuna C Uzochukwu Iruka N Okeke 2022-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010809 https://doaj.org/article/3cf047e0937c420ea77f476bc3e3709b EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010809 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010809 https://doaj.org/article/3cf047e0937c420ea77f476bc3e3709b PLoS Neglected Tropical Diseases, Vol 16, Iss 10, p e0010809 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010809 2022-12-30T21:43:40Z Background Enteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to dealing with persistent infection by these exceptional colonizers, which form copious biofilms. We screened the Medicines for Malaria Venture Pathogen Box for chemical entities that inhibit EAEC biofilm formation. Methodology We used EAEC strains, 042 and MND005E in a medium-throughput crystal violet-based antibiofilm screen. Hits were confirmed in concentration-dependence, growth kinetic and time course assays and activity spectra were determined against a panel of 25 other EAEC strains. Antibiofilm activity against isogenic EAEC mutants, molecular docking simulations and comparative genomic analysis were used to identify the mechanism of action of one hit. Principal findings In all, five compounds (1.25%) reproducibly inhibited biofilm accumulation by at least one strain by 30-85% while inhibiting growth by under 10%. Hits exhibited potent antibiofilm activity at concentrations at least 10-fold lower than those reported for nitazoxanide, the only known EAEC biofilm inhibitor. Reflective of known EAEC heterogeneity, only one hit was active against both screen isolates, but three hits showed broad antibiofilm activity against a larger panel of strains. Mechanism of action studies point to the EAEC anti-aggregation protein (Aap), dispersin, as the target of compound MMV687800. Conclusions This study identified five compounds, not previously described as anti-adhesins or Gram-negative antibacterials, with significant EAEC antibiofilm activity. Molecule, MMV687800 targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches against EAEC infection. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 16 10 e0010809 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 David A Kwasi Chinedum P Babalola Olujide O Olubiyi Jennifer Hoffmann Ikemefuna C Uzochukwu Iruka N Okeke Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background Enteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to dealing with persistent infection by these exceptional colonizers, which form copious biofilms. We screened the Medicines for Malaria Venture Pathogen Box for chemical entities that inhibit EAEC biofilm formation. Methodology We used EAEC strains, 042 and MND005E in a medium-throughput crystal violet-based antibiofilm screen. Hits were confirmed in concentration-dependence, growth kinetic and time course assays and activity spectra were determined against a panel of 25 other EAEC strains. Antibiofilm activity against isogenic EAEC mutants, molecular docking simulations and comparative genomic analysis were used to identify the mechanism of action of one hit. Principal findings In all, five compounds (1.25%) reproducibly inhibited biofilm accumulation by at least one strain by 30-85% while inhibiting growth by under 10%. Hits exhibited potent antibiofilm activity at concentrations at least 10-fold lower than those reported for nitazoxanide, the only known EAEC biofilm inhibitor. Reflective of known EAEC heterogeneity, only one hit was active against both screen isolates, but three hits showed broad antibiofilm activity against a larger panel of strains. Mechanism of action studies point to the EAEC anti-aggregation protein (Aap), dispersin, as the target of compound MMV687800. Conclusions This study identified five compounds, not previously described as anti-adhesins or Gram-negative antibacterials, with significant EAEC antibiofilm activity. Molecule, MMV687800 targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches against EAEC infection. |
format |
Article in Journal/Newspaper |
author |
David A Kwasi Chinedum P Babalola Olujide O Olubiyi Jennifer Hoffmann Ikemefuna C Uzochukwu Iruka N Okeke |
author_facet |
David A Kwasi Chinedum P Babalola Olujide O Olubiyi Jennifer Hoffmann Ikemefuna C Uzochukwu Iruka N Okeke |
author_sort |
David A Kwasi |
title |
Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. |
title_short |
Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. |
title_full |
Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. |
title_fullStr |
Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. |
title_full_unstemmed |
Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli. |
title_sort |
antibiofilm agents with therapeutic potential against enteroaggregative escherichia coli. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0010809 https://doaj.org/article/3cf047e0937c420ea77f476bc3e3709b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 10, p e0010809 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010809 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010809 https://doaj.org/article/3cf047e0937c420ea77f476bc3e3709b |
op_doi |
https://doi.org/10.1371/journal.pntd.0010809 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
16 |
container_issue |
10 |
container_start_page |
e0010809 |
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1766343070954029056 |