An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections
Abstract Scarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pent...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-21526-4 |
| _version_ | 1811336475667595264 |
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| author | Ohad Meir Fadia Zaknoon Amram Mor |
| author_facet | Ohad Meir Fadia Zaknoon Amram Mor |
| author_sort | Ohad Meir |
| collection | DOAJ |
| description | Abstract Scarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pentamer, decanoyl-bis.diaminobutyrate-aminododecanoyl-diaminobutyrate-amide (C10BBc12B), whose sub-maximal tolerated doses combinations with inefficient antibiotics demonstrated systemic efficacies in murine models of peritonitis-sepsis and urinary-tract infections. Attempts to shed light into the mechanism of action using membrane-active fluorescent probes, suggest outer-membrane interactions to dominate the pentamer’s adjuvant properties, which were not associated with typical inner-membrane damages or with delayed bacterial growth. Yet, checkerboard titrations with low micromolar concentrations of C10BBc12B exhibited unprecedented capacities in potentiation of hydrophobic antibiotics towards Gram-negative ESKAPE pathogens, with an apparent low propensity for prompting resistance to the antibiotics. Assessment of the pentamer’s potentiating activities upon efflux inhibition incites submission of a hitherto unreported, probable action mechanism implicating the pentamer’s de-facto capacity to hijack bacterial efflux pumps for boosting its adjuvant activity through repetitive steps including outer-membrane adhesion, translocation and subsequent expulsion. |
| first_indexed | 2024-04-13T17:40:05Z |
| format | Article |
| id | doaj.art-cfa701f62a5d46c6ad64b004ce8f4dd3 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T17:40:05Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cfa701f62a5d46c6ad64b004ce8f4dd32022-12-22T02:37:13ZengNature PortfolioScientific Reports2045-23222022-10-0112111510.1038/s41598-022-21526-4An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infectionsOhad Meir0Fadia Zaknoon1Amram Mor2Faculty of Biotechnology and Food Engineering, Technion – Israel Institute of TechnologyFaculty of Biotechnology and Food Engineering, Technion – Israel Institute of TechnologyFaculty of Biotechnology and Food Engineering, Technion – Israel Institute of TechnologyAbstract Scarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pentamer, decanoyl-bis.diaminobutyrate-aminododecanoyl-diaminobutyrate-amide (C10BBc12B), whose sub-maximal tolerated doses combinations with inefficient antibiotics demonstrated systemic efficacies in murine models of peritonitis-sepsis and urinary-tract infections. Attempts to shed light into the mechanism of action using membrane-active fluorescent probes, suggest outer-membrane interactions to dominate the pentamer’s adjuvant properties, which were not associated with typical inner-membrane damages or with delayed bacterial growth. Yet, checkerboard titrations with low micromolar concentrations of C10BBc12B exhibited unprecedented capacities in potentiation of hydrophobic antibiotics towards Gram-negative ESKAPE pathogens, with an apparent low propensity for prompting resistance to the antibiotics. Assessment of the pentamer’s potentiating activities upon efflux inhibition incites submission of a hitherto unreported, probable action mechanism implicating the pentamer’s de-facto capacity to hijack bacterial efflux pumps for boosting its adjuvant activity through repetitive steps including outer-membrane adhesion, translocation and subsequent expulsion.https://doi.org/10.1038/s41598-022-21526-4 |
| spellingShingle | Ohad Meir Fadia Zaknoon Amram Mor An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections Scientific Reports |
| title | An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections |
| title_full | An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections |
| title_fullStr | An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections |
| title_full_unstemmed | An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections |
| title_short | An efflux-susceptible antibiotic-adjuvant with systemic efficacy against mouse infections |
| title_sort | efflux susceptible antibiotic adjuvant with systemic efficacy against mouse infections |
| url | https://doi.org/10.1038/s41598-022-21526-4 |
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