Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens
ABSTRACT 12-Bis-THA Cl2 [12,12′-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to sh...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-02-01
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| Series: | mSphere |
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| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00508-22 |
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| author | Simona Di Blasio Maria Clarke Charlotte K. Hind Masanori Asai Louis Laurence Angelica Benvenuti Mahnoor Hassan Dorothy Semenya DeDe Kwun-Wai Man Victoria Horrocks Giorgia Manzo Sarah Van Der Lith Carolyn Lam Eugenio Gentile Callum Annette Janine Bosse Yanwen Li Barry Panaretou Paul R. Langford Brian D. Robertson Jenny K. W. Lam J. Mark Sutton Michael McArthur A. James Mason |
| author_facet | Simona Di Blasio Maria Clarke Charlotte K. Hind Masanori Asai Louis Laurence Angelica Benvenuti Mahnoor Hassan Dorothy Semenya DeDe Kwun-Wai Man Victoria Horrocks Giorgia Manzo Sarah Van Der Lith Carolyn Lam Eugenio Gentile Callum Annette Janine Bosse Yanwen Li Barry Panaretou Paul R. Langford Brian D. Robertson Jenny K. W. Lam J. Mark Sutton Michael McArthur A. James Mason |
| author_sort | Simona Di Blasio |
| collection | DOAJ |
| description | ABSTRACT 12-Bis-THA Cl2 [12,12′-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used. |
| first_indexed | 2024-04-10T09:01:12Z |
| format | Article |
| id | doaj.art-8625d87284694eff9568dd55269bba7a |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-04-10T09:01:12Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-8625d87284694eff9568dd55269bba7a2023-02-21T14:03:56ZengAmerican Society for MicrobiologymSphere2379-50422023-02-018110.1128/msphere.00508-22Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal PathogensSimona Di Blasio0Maria Clarke1Charlotte K. Hind2Masanori Asai3Louis Laurence4Angelica Benvenuti5Mahnoor Hassan6Dorothy Semenya7DeDe Kwun-Wai Man8Victoria Horrocks9Giorgia Manzo10Sarah Van Der Lith11Carolyn Lam12Eugenio Gentile13Callum Annette14Janine Bosse15Yanwen Li16Barry Panaretou17Paul R. Langford18Brian D. Robertson19Jenny K. W. Lam20J. Mark Sutton21Michael McArthur22A. James Mason23Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomTechnology Development Group, UK Health Security Agency, Research and Evaluation, Salisbury, United KingdomSection of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United KingdomNorwich Medical School, University of East Anglia, Norwich, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomSection of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United KingdomSection of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomSection of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United KingdomMRC Centre for Molecular Bacteriology and Infection, Department of Infectious Disease, Imperial College London, London, United KingdomDepartment of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong KongInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomNorwich Medical School, University of East Anglia, Norwich, United KingdomInstitute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King’s College London, London, United KingdomABSTRACT 12-Bis-THA Cl2 [12,12′-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used.https://journals.asm.org/doi/10.1128/msphere.00508-22dequalinium chloridesynergyaminoglycosidesGalleria mellonella |
| spellingShingle | Simona Di Blasio Maria Clarke Charlotte K. Hind Masanori Asai Louis Laurence Angelica Benvenuti Mahnoor Hassan Dorothy Semenya DeDe Kwun-Wai Man Victoria Horrocks Giorgia Manzo Sarah Van Der Lith Carolyn Lam Eugenio Gentile Callum Annette Janine Bosse Yanwen Li Barry Panaretou Paul R. Langford Brian D. Robertson Jenny K. W. Lam J. Mark Sutton Michael McArthur A. James Mason Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens mSphere dequalinium chloride synergy aminoglycosides Galleria mellonella |
| title | Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens |
| title_full | Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens |
| title_fullStr | Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens |
| title_full_unstemmed | Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens |
| title_short | Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens |
| title_sort | bolaamphiphile analogues of 12 bis tha cl2 are potent antimicrobial therapeutics with distinct mechanisms of action against bacterial mycobacterial and fungal pathogens |
| topic | dequalinium chloride synergy aminoglycosides Galleria mellonella |
| url | https://journals.asm.org/doi/10.1128/msphere.00508-22 |
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