Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria

Surendran, Amrutha; Turnbull, Agnes; Flockhart, Allen; Findlay-Greene, Fern; Nowosielska, Martyna; Morrison, Donald; Mincher, David J.; Donnellan, Samantha

Abstract

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.

Citation

Surendran, A., Turnbull, A., Flockhart, A., Findlay-Greene, F., Nowosielska, M., Morrison, D., Mincher, D. J., & Donnellan, S. (2024). Design of a new class of broad-spectrum therapeutics targeted to drug-resistant bacteria. All Life, 17(1), Article 2379309. https://doi.org/10.1080/26895293.2024.2379309

• Journal Article Type: Article
• Acceptance Date: Jun 13, 2024
• Online Publication Date: Jul 22, 2024
• Publication Date: 2024
• Deposit Date: Mar 28, 2024
• Publicly Available Date: Aug 6, 2024
• Print ISSN: 2689-5293
• Electronic ISSN: 2689-5307
• Publisher: Taylor & Francis
• Peer Reviewed: Not Peer Reviewed
• Volume: 17
• Issue: 1
• Article Number: 2379309
• DOI: https://doi.org/10.1080/26895293.2024.2379309
• Keywords: Antimicrobial resistance, drug design, methicillin-resistant Staphylococcus aureus, Mycobacterium smegmatis
• Publisher URL: https://www.tandfonline.com/journals/tfls21
• Related Public URLs: https://figshare.com/articles/dataset/Raw_and_supplementary_data_Design_of_a_new_class_of_broad-spectrum_therapeutics_targeted_to_drug-resistant_bacteria/25335139