The Diverse Activities and Mechanisms of the Acylphloroglucinol Antibiotic Rhodomyrtone: Antibacterial Activity and Beyond

Abstract

Background/Objectives: The rose myrtle Rhodomyrtus tomentosa is a medicinal plant used in traditional Asian medicine. The active compound in R. tomentosa leaf extracts is rhodomyrtone, a chiral acylphloroglucinol. Rhodomyrtone exhibits an impressive breadth of activities, including antibacterial, antiviral, antiplasmodial, immunomodulatory, and anticancer properties. Its antibacterial properties have been extensively studied. Methods: We performed a comprehensive literature review on rhodomyrtone and summarized the current knowledge about this promising acylphloroglucinol antibiotic and its diverse functions in this review. Results: Rhodomyrtone shows nano to micromolar activities against a broad range of Gram-positive pathogens, including multidrug-resistant clinical isolates, and possesses a unique mechanism of action. It increases membrane fluidity and creates hyperfluid domains that attract membrane proteins prior to forming large membrane vesicles, effectively acting as a membrane protein trap. This mechanism affects a multitude of cellular processes, including cell division and cell wall synthesis. Additionally, rhodomyrtone reduces the expression of inflammatory cytokines, such as TNF-α, IL-17A, IL1β, and IL8. Generally showing low toxicity against mammalian cells, rhodomyrtone does inhibit the proliferation of cancer cell lines, such as epidermal carcinoma cells. The primary mechanism behind this activity appears to be the downregulation of adhesion kinases and growth factors. Furthermore, rhodomyrtone has shown antioxidant activity and displays cognitive effects, such as decreasing depressive symptoms in mice. Conclusions: Rhodomyrtone shows great promise as therapeutic agent, mostly for antibacterial but also for diverse other applications. Yet, bottlenecks such as resistance development and a better understanding of mammalian cell toxictiy demand careful assessment.

Keywords: Rhodomyrtus tomentosa; acylphloroglucinol; antimicrobial activity; mode of action; natural product; plant-derived antimicrobials; rhodomyrtone.

Figure 1

Structures of acylphloroglucinols. (a) General structure of acylphloroglucinol compounds. (b) Structure of (R)-rhodomyrtone. (c) Structure of (S)-rhodomyrtone.

Figure 2

Structures of rhodomyrtone (a) and C7-modified rhodomyrtone derivatives with improved activity against S. aureus.

Figure 3

Effects of rhodomyrtone on bacterial cells. (a) Schematic overview of cellular effects. (b) Rhodomyrtone-induced vesicles visualized with structured illumination microscopy. (c) Vesicles visualized with transmission electron microscopy. Membranes were stained with Mitotracker green. (d) Trapping of the integral membrane protein MraY in rhodomyrtone-induced vesicles. Membranes were stained with FM5-95. Panels (b–d) show Bacillus subtilis cells and were reproduced from [25].

Figure 4

Structures of non-pore-forming membrane-active antimicrobials with well-characterized mechanisms. (a) cWFW (cycloRRRWFW), (b) MP196 (RWRWRW-NH₂), (c) daptomycin (N-Decanoyl-Trp–D-Asn–Asp–Thr–Gly–Orn–Asp–D-Ala–Asp–Gly–D-Ser–3-Me-Glu–Kyn), and (d) gramicidin S (cyclo(-Val-Orn-Leu-D-Phe-Pro-)₂).

Figure 5

Mechanism of action of rhodomyrtone and other membrane-active compounds on bacterial cell membranes. Figure partially adapted from [78].

Figure 6

Resistance mechanism of S. aureus against rhodomyrtone according to results by Nguyen et al. and Huang et al. [85,87]. Green arrows indicate upregulation.

Figure 7

Effects of rhodomyrtone on mammalian cells. (1) Immunomodulatory, (2) anticancer, (3) antioxidant, and (4) cognitive effects of rhodomyrtone. Red arrows indicate down-regulation.