What is it all about?
Naringenin is a natural plant substance (a flavanone) that is mainly found in citrus fruits such as grapefruit, orange and pomelo – usually as the precursor “naringin”, which is converted into the active naringenin by intestinal bacteria. In addition to antioxidant and anti-inflammatory effects, naringenin also has antimicrobial properties. This review summarizes what is known about its effect against antibiotic-resistant bacteria (e.g. MRSA) and fungi – including mechanistic explanations and data on chemical derivatives (modified naringenin molecules), which often have a significantly stronger effect.
How does it work?
Directly against germs: Naringenin can disrupt bacterial membranes, weaken attachment and biofilms and even reduce bacterial toxins (e.g. α-toxin of Staphylococcus aureus).
disrupt communication: It inhibits “quorum sensing” – the bacterial “group radio” system that controls virulence and biofilm.
bypass resistance: Among other things, it blocks efflux pumps (which otherwise channel antibiotics out of the cell) and interferes with fatty acid synthesis.
What is special?
The activity against Gram-positive germs (e.g. S. aureus/MRSA) is usually stronger than against Gram-negative germs. Chemically modified naringenin derivatives achieve low MIC values for MRSA (4-64 µg/mL) and show synergy with antibiotics (e.g. gentamicin, erythromycin, sometimes oxacillin).
The effect against Gram-negatives (e.g. E. coli, P. aeruginosa, H. pylori) is more variable; Table 1 (p. 12-13) shows ranges from very low to high MICs.
Antifungal: There is moderate activity against Candida and molds; some derivatives are significantly more potent.
Important to know:
The evidence comes mainly from laboratory and animal data; there are no registered human clinical studies on anti-infective use.
Safety/bioavailability: Only approx. 15 % is absorbed orally; single-ascending dose data show up to 900 mg to be safe. Interactions (e.g. via liver enzymes) in combination with antibiotics should be considered.
Brief conclusion: Promising as a supplement to antibiotic therapy (especially in combination).
Background
The increase in multi-resistant pathogens (MRSA, VRE, ESBL/KPC/NDM-forming Gram-negatives) and the lack of new active substances create a need for adjuvant strategies. Naringenin (5,7,4′-trihydroxyflavanone) is a common citrus flavanone (in vivo mostly microbially deconjugated from the glycoside naringin ) with documented antioxidant, anti-inflammatory and antimicrobial effects.
This review consolidates data on the antibacterial and antifungal activity of naringenin and derivatives as well as on the mechanisms of action and combination potential with antibiotics.
Chemistry, occurrence, pharmacokinetics and safety
Naringenin/naringin are detectable in grapefruit, oranges, pomelo, etc.; concentrations vary depending on variety, fruit part and processing (e.g. high naringin content in membranes/albedo; pressed vs. manually pressed juices differ significantly). Oral bioavailability is limited(~15 % absorption). Clinical safety data show good tolerability up to 900 mg in single-ascending dose studies.
Antifungal activity
Naringenin shows moderate effects against yeasts and molds (e.g. Candida albicans, Aspergillus niger), while certain C-3-substituted or O-alkyl/oxime derivatives significantly increase potency (e.g. MIC 16-24 µg/mL). Combinations with fluconazole showed synergy against fluconazole-resistant C. albicans.
Mechanisms of action (summary)
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Membrane destabilization and increase in permeability (Gram+ more pronounced).
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QS inhibition (LasI/R & RhlI/R in P. aeruginosa), biofilm genes(icaAD, gtfB/C, luxS, etc.) ↓.
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Fatty acid/cell envelope synthesis: Inhibition of 3-hydroxyacyl-ACP dehydratase(H. pylori) and 3-ketoacyl-ACP synthase(Enterococcus).
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Efflux pump inhibition (e.g. CmeABC in Campylobacter).
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Toxin reduction (S. aureus α-toxin ).
These targets, which differ from classic antibiotics, explain synergies observed with numerous classes (β-lactams, aminoglycosides, fluoroquinolones, macrolides, etc.).
Limitations and outlook
The evidence is mainly based on in vitro/animal data; controlled human studies on anti-infective efficacy are lacking. Pharmacokinetics (absorption/metabolism), standardization of active derivatives/extracts, dose-finding studies and interaction/safety testing (including potential influence on drug metabolism) are prerequisites for translation. Despite these hurdles, broad mechanisms and combination potentials speak in favor of further developing naringenin derivatives as adjuvant anti-infectives – especially against biofilm-associated and resistant pathogens.