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. 2024 Jun 2;25(11):6140.
doi: 10.3390/ijms25116140.

The Multifaceted Actions of PVP-Curcumin for Treating Infections

Magdalena Metzger  1   2   3 , Stefan Manhartseder  1   2 , Leonie Krausgruber  1   2 , Lea Scholze  1   2 , David Fuchs  1   2 , Carina Wagner  1   2 , Michaela Stainer  1   2 , Johannes Grillari  1   2   3 , Andreas Kubin  4 , Lionel Wightman  4 , Peter Dungel  1   2
Affiliations

The Multifaceted Actions of PVP-Curcumin for Treating Infections

Magdalena Metzger et al. Int J Mol Sci. .

Abstract

Curcumin is a natural compound that is considered safe and may have potential health benefits; however, its poor stability and water insolubility limit its therapeutic applications. Different strategies aim to increase its water solubility. Here, we tested the compound PVP-curcumin as a photosensitizer for antimicrobial photodynamic therapy (aPDT) as well as its potential to act as an adjuvant in antibiotic drug therapy. Gram-negative E. coli K12 and Gram-positive S. capitis were subjected to aPDT using various PVP-curcumin concentrations (1-200 µg/mL) and 475 nm blue light (7.5-45 J/cm2). Additionally, results were compared to aPDT using 415 nm blue light. Gene expression of recA and umuC were analyzed via RT-qPCR to assess effects on the bacterial SOS response. Further, the potentiation of Ciprofloxacin by PVP-curcumin was investigated, as well as its potential to prevent the emergence of antibiotic resistance. Both bacterial strains were efficiently reduced when irradiated with 415 nm blue light (2.2 J/cm2) and 10 µg/mL curcumin. Using 475 nm blue light, bacterial reduction followed a biphasic effect with higher efficacy in S. capitis compared to E. coli K12. PVP-curcumin decreased recA expression but had limited effect regarding enhancing antibiotic treatment or impeding resistance development. PVP-curcumin demonstrated effectiveness as a photosensitizer against both Gram-positive and Gram-negative bacteria but did not modulate the bacterial SOS response.

Keywords: antimicrobial photodynamic therapy; antimicrobial resistance; bacterial SOS response.

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Conflict of interest statement

A.K. and L.W. are staff members of the company PLANTA Naturstoffe Vertriebs GmbH, which provided the molecule PVP–curcumin used in the present study. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Antibacterial effects of photodynamic therapy using blue light (475 nm). (A) When the Gram-negative bacterial strain E. coli K12 was irradiated with 15 J/cm2, it was most efficiently decreased with 10 µg/mL curcumin (LRV = 1.09, 91.83%, p < 0.0001). Higher concentrations were less effective. Curcumin concentrations of up to 200 µg/mL did not affect bacterial growth without photoactivation. (B) Colony-forming units (CFUs) of S. capitis were already decreased by 1.9-log10 units (98.76%, p = 0.81) when irradiated with 15 J/cm2 after incubation with 1 µg/mL curcumin. Compared to E. coli K12, aPDT efficacy using 10 µg/mL curcumin was higher in S. capitis with LRV = 4.76 (99.998%, p = 0.0038). Antibacterial effects of aPDT decreased with 200 µg/mL curcumin (LRV = 2.04, 99.1%, p = 0.7544). Increasing the light dose when treating bacterial cells with 10 µg/mL curcumin enhanced therapy outcome (C,D). A total of 15 and 45 J/cm2 of 475 nm blue light alone did not have an effect on the growth of neither E. coli K12 nor S. capitis. Mean ± SEM, n = 3–10, Kruskal–Wallis test with Dunn’s multiple comparisons test, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001.
Figure 2
Figure 2
aPDT with 10 µg/mL curcumin and 2.2 J/cm2 of 415 nm blue light. CFUs of E. coli K12 were significantly reduced by aPDT (LRV = 4.26, 99.994%, p = 0.0027) but not by 415 nm blue light alone. Similarly, a decrease of 7.0-log10 units (99.99999%, p = 0.0023) was observed in S. capitis. This Gram-positive bacterial strain was also not affected by 415 nm blue light alone. Mean ± SEM, n = 4, Kruskal–Wallis test with Dunn’s multiple comparisons test, ** p ≤ 0.01.
Figure 3
Figure 3
Gene expression of recA and umuC after pre-incubation of E. coli K12 with PVP–curcumin and subsequent Ciprofloxacin treatment. (A) PVP–curcumin had little effect on the expression of the gene recA in non-stressed cells with a slight decrease in expression when exposed to 50 µg/mL curcumin (2−ΔΔCt = 0.62, p > 0.9999). When a sublethal dose of Ciprofloxacin was added, the expression increased on average 163.73-fold (p = 0.049). This effect was less pronounced when cells were first pre-treated with 10 µg/mL curcumin (2−ΔΔCt = 16.91, p = 0.3465) and 50 µg/mL curcumin (2−ΔΔCt = 37.93, p = 0.2803). (B) There was no increase in umuC expression detected among all experimental groups. Housekeeping gene: yccT. Box and whisker blots indicating median, minimum and maximum values, Kruskal–Wallis test, Dunn’s multiple comparison test, ROUT method outlier test, n = 5, * p ≤ 0.05.
Figure 4
Figure 4
Potentiation of sublethal Ciprofloxacin treatment in E. coli K12. A minor increase from 1.81- to 2.4-log10 units of antibacterial efficacy was observed when cells were pre-treated with 10 µg/mL curcumin for 60 min. Ctrl indicates an untreated control group, Cur stands for curcumin and Cipro only stands for Ciprofloxacin treatment. Kruskal–Wallis test, Dunn’s multiple comparison test, n = 3, ** p ≤ 0.01.
Figure 5
Figure 5
The impact of PVP–curcumin on Ciprofloxacin resistance development in E. coli K12. (A) The bacterial strain was treated every day with a sublethal dose of Ciprofloxacin and/or PVP–curcumin (either 10 or 50 µg/mL curcumin) and cultivated further in fresh medium. Every third day, CFUs were determined after treatment to assess bacterial growth and the efficacy of the antibiotic. While after six days, the antibacterial effect of Ciprofloxacin was reduced, there was no difference whether cells were pre-treated with PVP–curcumin or not. Values depicted are normalized to the starting bacterial concentration of 1 × 107 CFU. (B) Expression of the bacterial SOS response initiator protein RecA—indicated as 2−ΔΔCt—was not significantly different in the overnight cultures of any of the treatment groups. (C) Likewise, umuC gene expression stayed consistent over the duration of 15 days in all conditions. Two-way ANOVA, Fisher’s least significant difference test, mean ± SD, n = 3, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.
Figure 6
Figure 6
Experimental setup to test the influence of PVP–curcumin on antibiotic resistance development. (1) On day 0, the optical density of a planktonic overnight culture of E. coli K12 was determined and six microcentrifuge tubes were prepared, each containing the desired cell concentration. (2) PVP–curcumin was added to the respective tubes to reach a curcumin concentration of 10 or 50 µg/mL. Bacterial cells were incubated for 20 min at 37 °C. (3) Three tubes were treated with 0.4 µg/mL Ciprofloxacin for 10 min. Additionally, on day 0 as well as every third day, each experimental group was serially diluted 1:10 for the quantification of bacterial cell numbers after the treatments. Next, three drops of each dilution were transferred to agar plates and incubated at 37 °C overnight. (4) Immediately after antibiotic treatment, vented tubes filled with 1 mL culture medium were inoculated with a 10 µL aliquot of the respective experimental group. Every third day, the rest of the overnight cultures were harvested for qPCR analysis. (5) At the beginning of each day, the optical density of all individual tubes was measured to assess the cell number. Image created with Biorender.com.
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