Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria
We hypothesise that antimicrobial resistance (AMR) cannot be overcome by simply ‘drugging’ single biological targets, therefore, our focus is developing broad-spectrum therapeutics. Herein we present the synthesis of two novel spacer-linked, anthraquinone-triphenylphosphonium (AQ-TPP) conjugates (4)...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | All Life |
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| Online Access: | http://dx.doi.org/10.1080/26895293.2024.2379309 |
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| author | Amrutha Surendran Agnes Turnbull Allen Flockhart Fern Findlay-Greene Martyna Nowosielska Donald Morrison David J. Mincher Samantha Donnellan |
| author_facet | Amrutha Surendran Agnes Turnbull Allen Flockhart Fern Findlay-Greene Martyna Nowosielska Donald Morrison David J. Mincher Samantha Donnellan |
| author_sort | Amrutha Surendran |
| collection | DOAJ |
| description | We hypothesise that antimicrobial resistance (AMR) cannot be overcome by simply ‘drugging’ single biological targets, therefore, our focus is developing broad-spectrum therapeutics. Herein we present the synthesis of two novel spacer-linked, anthraquinone-triphenylphosphonium (AQ-TPP) conjugates (4) and (5) as early lead compounds in a new class of agent designed to penetrate the lipophilic barriers of the membranes of a diverse family of species; and establish bacterial growth inhibitory properties against methicillin-resistant Staphylococcus aureus (NCTC 13616) and Mycobacterium smegmatis [mc2155] (as a surrogate for Mycobacterium tuberculosis). The MIC and MBC values of (4) and (5) were determined against MRSA and found to be equipotent [MIC for each: 1 µg/mL (1.2 µM)]. Whereas the amide-linked conjugate (5) was determined to have 2-fold greater bactericidal potency [MBC 1 µg/mL (1.2 µM] than ester-linked (4). The anthraquinone-TPP conjugates (4) and (5) were active in vitro against Mycobacterium smegmatis (graphical abstract) and were equipotent as determined by their MIC values; in contrast to MRSA, the less hydrophobic (4) had 2-fold greater bactericidal potency than (5) as measured by their MBC values. Notably, both conjugates showed potent intracellular growth inhibitory activity in infected THP-1 macrophages. The conjugates are promising leads for the development of new antibacterial drugs. Key policy highlights Development of a novel class of antimicrobial compounds Drug screen against a WHO ‘high’ priority drug-resistant pathogen that poses the greatest threat to human health (methicillin-resistant Staphylococcus aureus) Drug screen against a surrogate for Mycobacterium tuberculosis, one of the leading causes of mortality worldwide. |
| format | Article |
| id | doaj-art-ebb787cff8494e1cb3c68429d104f5d3 |
| institution | Kabale University |
| issn | 2689-5307 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | All Life |
| spelling | doaj-art-ebb787cff8494e1cb3c68429d104f5d32025-01-20T14:38:00ZengTaylor & Francis GroupAll Life2689-53072024-12-01170110.1080/26895293.2024.23793092379309Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteriaAmrutha Surendran0Agnes Turnbull1Allen Flockhart2Fern Findlay-Greene3Martyna Nowosielska4Donald Morrison5David J. Mincher6Samantha Donnellan7Edinburgh Napier UniversityEdinburgh Napier UniversityEdinburgh Napier UniversityEdinburgh Napier UniversityEdinburgh Napier UniversityEdinburgh Napier UniversityEdinburgh Napier UniversityEdinburgh Napier UniversityWe hypothesise that antimicrobial resistance (AMR) cannot be overcome by simply ‘drugging’ single biological targets, therefore, our focus is developing broad-spectrum therapeutics. Herein we present the synthesis of two novel spacer-linked, anthraquinone-triphenylphosphonium (AQ-TPP) conjugates (4) and (5) as early lead compounds in a new class of agent designed to penetrate the lipophilic barriers of the membranes of a diverse family of species; and establish bacterial growth inhibitory properties against methicillin-resistant Staphylococcus aureus (NCTC 13616) and Mycobacterium smegmatis [mc2155] (as a surrogate for Mycobacterium tuberculosis). The MIC and MBC values of (4) and (5) were determined against MRSA and found to be equipotent [MIC for each: 1 µg/mL (1.2 µM)]. Whereas the amide-linked conjugate (5) was determined to have 2-fold greater bactericidal potency [MBC 1 µg/mL (1.2 µM] than ester-linked (4). The anthraquinone-TPP conjugates (4) and (5) were active in vitro against Mycobacterium smegmatis (graphical abstract) and were equipotent as determined by their MIC values; in contrast to MRSA, the less hydrophobic (4) had 2-fold greater bactericidal potency than (5) as measured by their MBC values. Notably, both conjugates showed potent intracellular growth inhibitory activity in infected THP-1 macrophages. The conjugates are promising leads for the development of new antibacterial drugs. Key policy highlights Development of a novel class of antimicrobial compounds Drug screen against a WHO ‘high’ priority drug-resistant pathogen that poses the greatest threat to human health (methicillin-resistant Staphylococcus aureus) Drug screen against a surrogate for Mycobacterium tuberculosis, one of the leading causes of mortality worldwide.http://dx.doi.org/10.1080/26895293.2024.2379309antimicrobial resistancedrug designmethicillin-resistant staphylococcus aureusmycobacterium smegmatis |
| spellingShingle | Amrutha Surendran Agnes Turnbull Allen Flockhart Fern Findlay-Greene Martyna Nowosielska Donald Morrison David J. Mincher Samantha Donnellan Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria All Life antimicrobial resistance drug design methicillin-resistant staphylococcus aureus mycobacterium smegmatis |
| title | Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria |
| title_full | Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria |
| title_fullStr | Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria |
| title_full_unstemmed | Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria |
| title_short | Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria |
| title_sort | design of a new class of broad spectrum therapeutics targeted to drug resistant bacteria |
| topic | antimicrobial resistance drug design methicillin-resistant staphylococcus aureus mycobacterium smegmatis |
| url | http://dx.doi.org/10.1080/26895293.2024.2379309 |
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