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. 2024 Feb 3;64(4):1619–1626. doi: 10.1007/s12088-024-01196-8

Antimicrobial Effect of Diphenyl Ditelluride (PhTe)2 in a Model of Infection by Escherichia coli in Drosophila melanogaster

Franciane Cabral Pinheiro 1, Vandreza Cardoso Bortolotto 1, Stífani Machado Araujo 2, Mustafa Munir Mustafa Dahleh 1, José Sebastião Santos Neto 5, Gilson Zeni 3, Arnaldo Zaha 4, Marina Prigol 1,✉
PMCID: PMC11645334  PMID: 39678956

Abstract

Diphenyl ditelluride (PhTe)2, an organotelluric compound with pharmacological and toxicological attributes, has shown promise in microorganism studies. Drosophila melanogaster, an alternative animal model, is gaining popularity for novel antimicrobial research due to its cost-effectiveness, versatility, and similarity to vertebrate models. Given the rising antibiotic resistance, particularly in Escherichia coli (E. coli), the exploration of novel antimicrobials is of utmost importance. In (PhTe)2 safety validation, our findings indicate an 50% lethal concentration (LC50) of 41.74 µM for (PhTe)2 following a 48-h exposure period in Drosophila melanogaster. To assess potential motor and neurological deficits, we conducted behavioral analyses employing negative geotaxis and open field tests. Our outcomes reveal alterations in exploratory behavior at concentrations exceeding 50 µM (PhTe)2 in the flies. Consequently, we have established the optimal treatment concentration for Drosophila melanogaster as 10 µM (PhTe)2. Upon safety validation, we gauged the antimicrobial potential of (PhTe)2 through an oral infection model involving axenic flies. After exposing these flies to E. coli for 18–20 h, we treated them with 10 µM of (PhTe)2 for various time spans (0, 3, 6, 12, 24, and 48 h), followed by plating and colony counting. The logarithmic bacterial load curve demonstrated the antimicrobial impact of the compound, highlighting a significant reduction in bacterial load after 3 h of exposure to 10 µM (PhTe)2, with an enhancement of antimicrobial potential lasting up to 48 h. Given these results, we state that 10 µM (PhTe)2 was safe and presented antimicrobial potential, reducing the bacterial load in Drosophila melanogaster.

Graphical Abstract

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Keywords: Antimicrobial, Organotellurium compound, Drosophila melanogaster, Oral infection, Escherichia coli

Introduction

Since 1940, antibiotics have been crucial antimicrobial agents inhibiting microbial growth and widely used to treat bacterial infections in humans and animals [27]. However, their excessive use has led to increased antibiotic excretion and environmental release, driving bacterial drug resistance [21]. In 2019, antibiotic resistance caused approximately 1.27 million deaths, with six pathogens responsible for over 250,000 deaths: Escherichia coli (E. coli), Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Notably, E. coli was the primary contributor to antibiotic resistance-related deaths [13, 14]. E. coli, gram-negative bacteria of the Enterobacteriaceae family, reside in the human intestinal microbiota and can cause various diseases [15]. With numerous strains, they cause illnesses ranging from mild gastroenteritis to severe renal failure and septic shock. Their virulence enables them to resist host defenses and antibiotics [7]. Thus, developing new strategies for combating multidrug-resistant pathogens, including E. coli, is crucial [4, 19].

In this sense, compounds such as diphenyl ditelluride (PhTe)2, an organic derivative of tellurium, which has already been described as having antigenotoxic, antimutagenic and anticancer properties, have become the target of studies, due to its pro-oxidant and antioxidant properties [16]. On one hand, it can trigger oxidative stress by generating reactive oxygen species, inducing biological harm in targeted cells. On the other hand, its antioxidant qualities neutralize free radicals through reactive oxygen species compensation. These multifaceted properties position (PhTe)2 as a promising strategy against microbial resistance [10, 24]. In an in vitro study carried out by Pinheiro et al., [16] it was possible to observe an antimicrobial effect of (PhTe)2 against E. coli, therefore the evaluation of its in vivo activity became necessary since the infection in vivo provides greater understanding of growth dynamics thwarted by host innate immunity, possible changes in host danger sensing, and manipulation of innate immunity [17, 19].

Drosophila melanogaster is a valuable in vivo model for studying antimicrobial responses, offering insights into innate immunity without acquired immunity complexities [9, 23]. Research on Drosophila Immune deficiency (Imd) and Toll-like receptor (Toll) pathways reveals mechanisms underlying innate immunity [11]. The Imd pathway responds to Gram-negative bacteria, while the Toll pathway activates against fungi and Gram-positive bacteria [11]. These pathways coordinate antimicrobial peptides and immune effectors [25], exemplified in studies on pathogens like Serratia marcescens, Erwinia carotovora, and E. coli [12, 25].

Based in aforementioned factors, Drosophila melanogaster stands as an excellent model for studying bacterial infections. Notably, conventional infection experiments entail introducing bacteria via a needle immersed in a concentrated bacterial solution [20]. In our study, in pursuit of enhanced reproducibility, we opted for the oral infection method for Drosophila [22]. Thus, our study aimed to evaluate the antimicrobial effect of (PhTe)2, in a model of oral infection of E. coli in Drosophila melanogaster.

Materials and Methods

Chemical

Diphenyl ditelluride (PhTe)2 was prepared according to the method previously published by Petragnani (1994) (Fig. 1). The 1Proton Nuclear Magnetic Resonance (1H-NMR) and Carbon-13 nuclear magnetic resonance (C-13 NMR) spectra analysis showed analytical and spectroscopic data in full agreement with their assigned structure; Gas chromatography/High-Performance Liquid Chromatography (GC/HPLC) determined the chemical purity of (PhTe)2 (99.9%), which was diluted with dimethyl sulfoxide (DMSO).

Fig. 1.

Fig. 1

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Chemical structure of the compound diphenyl ditelluride (PhTe)2

Drosophila melanogaster and Escherichia coli Stock and Culture

Drosophila melanogaster (Harwich strain) of the wild type was obtained from Laftambio (Unipampa, Itaqui-RS). The flies were kept in glass flasks, under controlled temperature of 25 ± 1 °C, humidity of 60–70% and circadian cycle light/dark of 12 h, fed with standard food composed of corn flour (76,59%, w/w), wheat germ (8,51%, w/w), sugar (7,23%, w/w), milk powder (7,23%, w/w), salt (0.43%, w/w) and Nipagin (antifungal). The bacterial strain used in this study is E. coli BL21 (DE3) RIL (B F– ompT hsdS(rB –mB–) dcm + Tet(r) gal endA Hte [argU ileY leuW Cam(r), from Biotechnology Center (CBiot)/UFRGS. The strain was kept frozen in 10% glycerol (v/v) until use.

Diphenyl Ditelluride (PhTe)2 Safety Evaluation in Drosophila melanogaster

To determine (PhTe)2 safe concentrations for the study, we started with concentrations of 1, 10, 25, 50, 100 and 200 µM of the compound, diluted in dimethylsulfoxide (DMSO) at 0.1% (v/v) of the total volume. The different concentrations of (PhTe)2 were mixed with 10 ml of the standard diet and homogenized, two control groups were used, one without the compound (PhTe)2 and vehicle; and the other control only with the vehicle (DMSO) at 0.1%. For each group, 50 flies of both sexes kept (50% females, 50% males) were kept in standard medium, under conditions of 25 ± 1 °C, in a light/dark cycle of 12:12 h with ~ 60% of humidity. To determine the safety of the compound determined by 50% lethal concentration (LC50) and behavioral tests were evaluated after 48 h of exposure.

Survival Curve

After the start of treatment, survival counted every day until the end of the 48 h, the diet changed every day and dead flies were discarded. Mortality rate analysis performed at 48 h to determine the safety of the compound. To determine the safety of the compound we determined the LC50.

Behavioral Test

Negative geotaxis test: A negative geotaxis test was performed to assess possible behavioral changes related to hyperactivity in flies, which can determine the locomotor function of flies. The test was performed with 20 flies from each experimental group, and the time required to reach the 8 cm of the tube was counted, according to Araujo et al. [2]. The test was repeated five times for each fly, and data were expressed as the average of five trials in the treatment group. For each repetition, a 5-min interval was included, and the experiment was carried out on the same day for all experimental groups.

Open Field Test The open field test was used to assess the locomotor activity of flies, as in the study by Hirth [6]. Flies after 48 h of treatment were kept in a 9 cm diameter arena that was divided into squares (11 cm), and the area was covered with a Petri dish. The activities and movements of the flies were timed, and the trajectory was recorded at a given time (60 s). Results are expressed as the average number of squares crossed by the group of flies. About 20 flies per group were included in this test.

Oral Infection and Treatment with Diphenyl Ditelluride

Bacteria Preparation

Escherichi coli strains Bl 21-DE RIL, these were kept in standard Lauria Bertani Broth (LB) at 37 °C, ± 150 rpm overnight, an aliquot was transferred to 50 ml of new LB until reaching the OD600 0.6–0.8, were centrifuged at 2,500×g for 15 min at 4 °C, the supernatant was discarded, and the pellet was resuspended in a 5% sucrose water solution (w/v).

Preparation of the Fly for Exposure

To obtain axenic flies for the study, eggs were first collected in sterile apple agar medium (1 L of distilled H2O, 30 g of agar, 33 g of sucrose, 330 ml of apple juice and Nipagin antifungal agent) with yeast for 24 h. Then the collected eggs were washed 3 × in a 10% sodium hypochlorite solution (w/v), interspersed with washing in phosphate buffered saline (PBS) 1X. After the cleaning and asepsis process, the eggs were transferred to flasks containing Lewis standard medium (1 L triple distilled H2O, 6.1 g agar, 93.6 g brown sugar, 68 g maize, 18.7 g instant yeast, 10 g Nipagin antifungal agent), sterile, and incubators at 25 ± 1 °C, on a 12:12 h light/dark cycle with ~ 60% humidity. After hatching, 2–3-day old flies were used for the experiments (Fig. 2) [22].

Fig. 2.

Fig. 2

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Experimental design of the study

Oral Infection Model and (PhTe)2 Treatment

For infection model we used the methodology of Siva-Jothy et al. [22] (Fig. 2), where flies were hunger 2–4 h before exposure to the bacteria. Sterile 40 ml falcon vials were placed, where 500 µL of standard sugar agar was pipetted into the cap and allowed to dry, then sterile filter paper discs were placed on the agar and 100 µL of bacterial culture at OD600 0.5–0.8, were pipetted directly onto filter paper (85 g/m2 grammage, Unifil®, code 504012). The seven flies were exposed individually and remained in contact with the bacterial solution between 18 and 20 h at 25 °C, in a light/dark cycle of 12:12 h, with ~ 60% humidity. In the control (without infection), the bacterial solution was replaced in the same volume by a 5% (w/v) sucrose aqueous solution on filter paper, and incubated again at 25 °C, in a light/dark cycle of 12:12 h, with ~ 60% of humidity (Fig. 2).

At the end of the exposure time to the bacteria, a sample of two flies per group was seeded to confirm contamination. The flies were divided into four groups: (1) Without Infection; (2) Infection for E. coli + vehicle; (3) Infection for E. coli + 10 µM (PhTe)2; (4) Infection for E. coli. Each group consisted of five flies placed in flasks containing 10 ml of agar (2% sucrose, 1% milk powder, 1% agar; 0.08% Nipagin). The flies were exposed to the compound during times of 0, 3, 6, 12, 24 and 48 h. The experiments were performed in experimental triplicate. After exposure to the compound, flies were washed immediately after bacterial exposure by placing them in 100 μL of 70% ethanol for ± 20–30 s, after which the ethanol was drained. Subsequently, 100 μL of distilled water was introduced for an equivalent duration, repeating the washing cycle thrice. Once the rinsing was completed, the water was removed, and 100 µL of 1X PBS was introduced and thoroughly mixed.

Microbiological Analysis

The homogenate was transferred to a 96-well plate and 90 µL of 1X PBS was added to each well, the samples were serially diluted, after which 5 µL of each serial dilution were seeded in nutrient LB agar and subsequently incubated for 24 h at 37 °C. The CFU (colony-forming unit) count per fly was determined by enumerating the colonies within the serial dilution. The colony count was then multiplied by the dilution factor to estimate the probable number of bacteria per fly. To statistically analyze the CFUs in the fly samples, the data was normalized and transformed logarithmically (log). Subsequently, generalized linear models were employed to assess the treatment groups. The experimental trials were conducted in triplicate.

Statistical Analysis

The results were verified for normality of distribution by the Shapiro–Wilk test and homogeneity by the Brown–Forsythe test. Results were compared using One-Way Analysis of Variance (ANOVA) and Tukey’s post-hoc for multiple comparisons. Descriptive data were expressed as mean ± standard error of mean (SEM). Values lower than 0.05 (p < 0.05) were considered statistically significant. All statistical analysis results were performed by the GraphPad Prism 9.1.2 software.

Results

Diphenyl Ditelluride (PhTe)2 Safety in Drosophila melanogaster

To define the safety of (PhTe)2, LC50 was determined based on the mortality rate using the same time interval as the mortality curve (Fig. 3). According to our results, we obtained an LC50 = 41.74 µM (PhTe)2 within a 48-h exposure period in Drosophila melanogaster.

Fig. 3.

Fig. 3

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Determination of LC50 of (PhTe)2: analysis of the lethal concentration of the compound that can cause 50% of deaths during exposure of flies to different concentrations (1, 10, 25, 50, 100 and 200 µM) within 48 h. Values are provided as mean ± SEM (n = 6 for each group), following 95% confidence interval

Evaluation of (PhTe)2 Effect on Behavior of Drosophila melanogaster

Behavioral tests of negative geotaxis and open field were performed to determine the safety of (PhTe)2. In the negative geotaxis test, no statistical differences were observed between groups (Fig. 4A). Regarding the open field test, we observed that the concentrations of 50, 100 and 200 μM (PhTe)2 significantly reduced the exploratory capacity of the flies, when compared to the control (One-way ANOVA; F (7, 16) = 65.39; p < 0.0001; Fig. 4B). Based on the results obtained, we consider a concentration of 10 µM of (PhTe)2 to be safe for the treatment of the Drosophila melanogaster model orally infected with E. coli. Furthermore, this concentration represents roughly ¼ of the LC50 observed over the 48-h exposure period (41.74 µM).

Fig. 4.

Fig. 4

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Assessment of behavioral changes after exposure to different concentrations (1, 10, 25, 50, 100 and 200 µM) of (PhTe)2 for 48 h. A Negative geotaxis; B Open field. Values are provided as mean ± SEM (n = 3 for each group). Twenty adult flies (3–5 days old, male and female) were used for the test. Significance was determined by one-way analysis of variance (ANOVA) followed by the Tukey post hoc test. *Difference compared to the control group (p < 0.05); #Difference compared to the DMSO group (p < 0.05)

Antimicrobial Effect of (PhTe)2 in a Model of Oral Infection by E. coli in Drosophila melanogaster

To confirm E. coli growth capability in vivo, we exposed adult Drosophila melanogaster with axenic microbiota to oral infection by E. coli for 48 h. Subsequently, plate seeding was conducted to validate contamination. This observation substantiates the infective potential of E. coli in Drosophila melanogaster, demonstrating its active replication within adult flies.

Thus, we proceed to evaluate the antimicrobial potential of (PhTe)2, using a concentration of 10 µM, previously determined not to affect the behavior responses of Drosophila melanogaster. To quantify the bacterial load, the CFUs per fly were calculated from the number of colonies present in the lowest possible dilution to count the visible colonies, then the number of CFUs was multiplied by the present dilution factor, and thus we obtained the number of CFUs. For the statistical analysis and construction of the logarithmic curve, the CFUs of each fly were log-transformed. As a result, we obtained a log10 curve per CFU/fly. Statistical analysis revealed significant interactions between the groups [F(15,52) = 177.1, p = 0.0001; Fig. 5], where we can observe that the flies treated with 10 µM of (PhTe)2 had a significant reduction in the bacterial load over the exposure time, when compared to the Infection and Infection + Vehicle. For each experiment, 5 flies were used per group, and the experiments were performed in triplicate. Of note, the concentration of (PhTe)2 10 µM exhibited a proportional reduction in bacterial load over a span of 48 h of exposure, with statistical differences between groups (One-way ANOVA; F(5,13) = 689.0; p < 0.0001; Fig. 5).

Fig. 5.

Fig. 5

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Antimicrobial effect of (PhTe)2 in a model of oral infection in Drosophila melanogaster: Quantification of internal E. coli load in male and female flies following 48-h oral infection, *Significant difference compared with the Infection, Infection + Vehicle and Without infection; &Significant difference compared with the Infection + (PhTe)2 and Without infection; #Significant difference compared with the Infection, Infection + Vehicle and Infection + (PhTe)2; Significance was determined by one-way analysis of variance (ANOVA) followed by the Tukey post hoc test. Values are provided as mean ± SEM (n = 3 for each group); *Difference between the group and the control (p < 0.0001)

Discussion

Antimicrobial resistance has caused significant harmful effects on human health, contributing to increased mortality and infection rates due to the implementation of ineffective antibiotic dosages [1]. Concerns about E. coli infection is recurrent since it can harmlessly colonize the human intestine or cause intestinal or extra-intestinal infections, including serious invasive diseases such as bacteremia and sepsis, most common cause of bacteremia in high-income countries, and is a leading cause of meningitis in neonates [3]. Therefore, understanding the complex interactions that occur during a microbial infection is essential to advance knowledge of the pathophysiology of the infection, and therefore, in the development of new antimicrobial agents. In this study, we explored the antimicrobial effect of (PhTe)2, using Drosophila melanogaster as a model of oral infection by E. coli, evaluating host-microbe interactions. Promising results are obtained, such as reduction of the bacterial load of E. coli in axenic Drosophila melanogaster in different time spans.

Thus, the use of alternative animal models, such as the Drosophila melanogaster, has been widely used in studies to evaluate drug-microorganism interactions, since studies with vertebrate models are highly demanding and expensive [4, 26]. Drosophila species has innate immunity that involves cellular and humoral components, its cellular immune response involves phagocytosis, encapsulation and/or melanization of pathogens via hemocytes, plasmatocytes or crystalline cells, respectively. Humoral immunity involves the production of antimicrobial peptides through the Toll pathway (activated by gram-positive bacteria) or Imd pathway (activated by gram-negative bacteria) [28] making it a valid model of infection.

We initiated our investigation by assessing the toxicological safety of (PhTe)2 following its administration in our in vivo model. This approach was prompted since previous studies showing toxicological, antimicrobial, and antifungal capacity of (PhTe)2 in Saccharomyces cerevisiae yeast strains, and strains of bacteria such as Salmonella typhimurium [5, 8], and E. coli [16], exposed to different concentrations of (PhTe)2. To assess the antimicrobial potential of (PhTe)2 along with oral infection with E. coli, first a screening of concentrations that are not harmful to Drosophila melanogaster was carried out. Mortality rate outcomes revealed an LC50 = 41.74 µM (PhTe)2, and behavioral analysis revealed alterations in the exploratory capacity of the flies in open field test under higher concentrations (50, 100, and 200 µM), with a reduction in the exploratory activities of the flies. This result was not observed when flies were exposed to lower concentrations (1, 10, and 25 µM) in comparison to the control group. Based on these findings, we have determined that a concentration of 10 µM (PhTe)2 is the optimal choice for treating flies orally contaminated E. coli. This concentration represents a quarter of the LC50 value, ensuring its safety.

When we evaluated the antimicrobial potential of 10 µM (PhTe)2 in Drosophila melanogaster orally contaminated with E. coli, we found that the bacterial load progressively decreased over time in the treatment group and remained constant in the control group within 48 h. These results demonstrate that (PhTe)2 has antimicrobial potential at a concentration of 10 µM, thus this concentration is considered sufficient to inhibit microbial growth and additionally does not demonstrate lethality for the host organism.

We believe that the toxicological/antimicrobial potential of this compound is associated with its ability to oxidize sulfhydryl groups (–SH) of important biomolecules [18, 24], owing to its pro-oxidant and antioxidant attributes [16]. (PhTe)2 possesses the capacity to induce oxidative stress by generating reactive oxygen species, resulting in biological harm to targeted cells. Simultaneously, its antioxidant characteristics mitigate the impact of free radicals through compensatory reactive oxygen species. This becomes more evident when compared with our previous in vitro studies, when we identified a possible antimicrobial mechanism of (PhTe)2 on the E.coli, caused by increased levels of reactive species, lipid peroxidation, protein carbonylation and reduction of protein and non-protein thiols, in addition to altering the expression of the oxidative stress regulators soxS and oxyR, altering the antioxidant defense enzymes cycle, confirming the pro-oxidant potential of this compound [16]. Furthermore, within experiments involving the V79 cell line infected with strains of Saccharomyces cerevisiae, Salmonella typhimurium, and E. coli, subjected to several concentrations of (PhTe)2, it was observed that this compound also exhibited harmful effects against these microorganisms [5, 8, 16]. Finally, our data showed that E. coli can grow in adult flies with sterile microbiota, and (PhTe)2 is able to control the oscillatory nature of the bacterial load over time, thus suggesting that there is an active response of this compound against this infection thus proving its antimicrobial potential.

Conclusion

In summary, we demonstrate that (PhTe)2 can be considered a potential target for studies as an antimicrobial drug, since it proved to be effective in controlling the bacterial load in an in vivo model of oral infection without causing toxicity to Drosophila melanogaster. This discovery and the development of future multifaceted approaches exploiting the pro-oxidant and antioxidant potential of (PhTe)2 are needed to control pathogenicity against a growing list of multidrug-resistant pathogens such as E. coli.

Authors’ Contributions

FCB and MP designed the study. JSSN and GZ compound synthesis. FCB, VCB, SMA and MMMD conducted the safety validation and behavioral tests. FCB, VCB, SMA and MMMD analyzed the data and drafted the manuscript. AA and MP provided the main resources. SMA, MMMD and MP revised the manuscript. All authors contributed substantially to the study and approved the final version of the manuscript.

Funding

The authors are grateful for the financial support received from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (308120/2020-5), the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) (PQG 19/2551-0001913-0; 19/2551-0001975-0), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)—Financial Code 001 for the support and research grants provided.

Data Availability

The data that support the findings of this study are available from the corresponding author, upon request.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, upon request.

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