First Antibacterial Evaluation of an Anthraquinone–triphenylphosphonium Conjugate (SH1) against Sensitive and Drug-resistant Staphylococcus aureus and Escherichia coli
TL;DR
The results identify SH1 as a previously uncharacterised antibacterial agent active against MRSA and support the anthraquinone–DLC pharmacophore as a membrane-active scaffold warranting further structural optimisation.
Abstract
Background: Antimicrobial resistance (AMR) was directly attributable to an estimated 1.27 million deaths in 2019 and is projected to cause 1.91 million attributable deaths annually by 2050, creating sustained demand for antibacterial scaffolds that act through mechanisms distinct from conventional target inhibition. Anthraquinone–delocalised lipophilic cation (DLC) conjugates, in which a triphenylphosphonium (TPP⁺) or related cationic group drives electrostatic, membrane-targeted accumulation, are one such scaffold. SH1 (1-[(5-triphenylphosphonium-pentyl)oxy]anthraquinone) was previously synthesised and shown to accumulate selectively in the mitochondria of PC-3 prostate cancer cells, but its antibacterial activity has not previously been reported. Aim: To our knowledge, following a structured search of PubMed and Scopus that identified no prior antibacterial data for this compound, this study presents the first antibacterial evaluation of SH1. Methods: SH1 was assessed by broth microdilution in accordance with EUCAST guidelines against sensitive and drug-resistant strains of Staphylococcus aureus and Escherichia coli. Results: SH1 demonstrated a minimum inhibitory concentration (MIC) of 1.6 mg/L against both antibiotic-sensitive (NCTC 6571) and methicillin-resistant (NCTC 13616) S. aureus, with a minimum bactericidal concentration (MBC) of 3.2 mg/L, indicating equipotent bactericidal activity against MRSA. Against E. coli (ATCC 47055, sensitive; LIB213, resistant), SH1 showed an MIC and MBC of 25.6 mg/L for both strains. Conclusion: These results identify SH1 as a previously uncharacterised antibacterial agent active against MRSA and support the anthraquinone–DLC pharmacophore as a membrane-active scaffold warranting further structural optimisation. Halogenated analogues, including the arginine-conjugated derivative VO6 synthesised as part of this programme, remain candidates for future evaluation once solubility constraints are addressed. The study was limited to four bacterial strains, and comparator antibiotics were considered using published breakpoint data rather than side-by-side testing; these constraints are discussed further in the Limitations section.