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We demonstrate that medium‐chain fatty acids mimic the quorum‐sensing molecule farnesol. Six sets of evidence, that is, (i) structural similarities, (ii) inhibition of hyphal growth, (iii) inhibition of biofilm formation, (iv) inhibition of farnesol production, (v) inhibition of sterol production, and (vi) effects on gene expressions, which showed medium‐chain fatty acids interfere with farnesol signaling and that their antibiofilm and antivirulence activities are superior to that of farnesol. Our findings show that fatty acids found in prokaryotes and eukaryotes might interfere with fungal communication and that medium‐chain fatty acids might be used as developmental starting points for the design of potent antibiofilm and antifungal agents against fungal Candida species. Summary Candida biofilms are tolerant to conventional antifungal therapeutics and the host immune system. The transition of yeast cells to hyphae is considered a key step in C. albicans biofilm development, and this transition is inhibited by the quorum‐sensing molecule farnesol. We hypothesized that fatty acids mimicking farnesol might influence hyphal and biofilm formation by C. albicans. Among 31 saturated and unsaturated fatty acids, six medium‐chain saturated fatty acids, that is, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid and lauric acid, effectively inhibited C. albicans biofilm formation by more than 75% at 2 µg ml−1 with MICs in the range 100–200 µg ml−1. These six fatty acids at 2 µg ml−1 and farnesol at 100 µg ml−1 inhibited hyphal growth and cell aggregation. The addition of fatty acids to C. albicans cultures decreased the productions of farnesol and sterols. Furthermore, down‐regulation of several hyphal and biofilm‐related genes caused by heptanoic or nonanoic acid closely resembled the changes caused by farnesol. In addition, nonanoic acid, the most effective compound diminished C. albicans virulence in a Caenorhabditis elegans model. Our results suggest that medium‐chain fatty acids inhibit more effectively hyphal growth and biofilm formation than farnesol.

Candida albicans is frequently detected with heavy infection of Streptococcus mutans in plaque-biofilms from children affected with early-childhood caries, a prevalent and costly oral disease. The presence of C. albicans enhances S. mutans growth within biofilms, yet the chemical interactions associated with bacterial accumulation remain unclear. Thus, this study was conducted to investigate how microbial products from this cross-kingdom association modulate S. mutans build-up in biofilms. Our data revealed that bacterial-fungal derived conditioned medium (BF-CM) significantly increased the growth of S. mutans and altered biofilm 3D-architecture in a dose-dependent manner, resulting in enlarged and densely packed bacterial cell-clusters (microcolonies). Intriguingly, BF-CM induced S. mutans gtfBC expression (responsible for Gtf exoenzymes production), enhancing Gtf activity essential for microcolony development. Using a recently developed nanoculture system, the data demonstrated simultaneous microcolony growth and gtfB activation in situ by BF-CM. Further metabolites/chromatographic analyses of BF-CM revealed elevated amounts of formate and the presence of Candida -derived farnesol, which is commonly known to exhibit antibacterial activity. Unexpectedly, at the levels detected (25–50 μM), farnesol enhanced S. mutans -biofilm cell growth, microcolony development, and Gtf activity akin to BF-CM bioactivity. Altogether, the data provide new insights on how extracellular microbial products from cross-kingdom interactions stimulate the accumulation of a bacterial pathogen within biofilms.

Leishmaniasis is a zoonotic disease transmitted by an obligate intra-macrophage protozoan of the genus Leishmania through the infective bite of a vector sandfly. This study investigated the therapeutic efficacy of farnesol, a sesquiterpene compound, for the treatment of cutaneous leishmaniasis (CL) using in vivo BALB/c mouse model. In this study, farnesol’s efficacy was compared with the standard drug, paromomycin. It was observed that farnesol significantly reduced lesion sizes and footpad thickness compared to the control group (paromomycin). Lymph node size was also significantly reduced in farnesol-treated mice, indicating its ability to control infection spread. Combination therapy with farnesol and Paromomycin did not demonstrate synergistic effects. These results highlight the potential of farnesol as an alternative therapeutic agent for CL. Further investigations are required to elucidate its mechanism of action and assess potential off-target effects. Optimization of oral delivery methods should be explored to enhance bioavailability. Overall, our findings support farnesol’s efficacy in CL treatment, offering promising prospects for improved disease management.

The increasing emergence of antibiotics resistance is of global concern. Finding novel antimicrobial agents and strategies based on synergistic combinations are essential to combat resistant bacteria. We evaluated the activity of garvicin KS, a new bacteriocin produced by Lactococcus garvieae. The bacteriocin has a broad inhibitory spectrum, inhibiting members of all the 19 species of Gram-positive bacteria tested. Unlike other bacteriocins from Gram-positive bacteria, garvicin KS inhibits Acinetobacter but not other Gram-negative bacteria. Garvicin KS was tested in combination with other antimicrobial agents. We demonstrated synergy with polymyxin B against Acinetobacter spp. and Escherichia coli, but not against Pseudomonas aeruginosa. Similar effects were seen with mixtures of nisin and polymyxin B. The synergistic mixtures of all three components caused rapid killing and full eradication of Acinetobacter spp. and E. coli. In addition, garvicin KS and nisin also acted synergistically against Staphylococcus aureus, indicating different in modes of action between the two bacteriocins. Both bacteriocins showed synergy with farnesol, and the combination of low concentrations of garvicin KS, nisin and farnesol caused rapid eradication of all the S. aureus strains tested. Its broad inhibitory spectrum, rapid killing, and synergy with other antimicrobials makes garvicin KS a promising antimicrobial.

Isoprenoids are the output of the polymerization of five-carbon, branched isoprenic chains derived from isopentenyl pyrophosphate (IPP) and its isomer, dimethylallyl pyrophosphate (DMAPP). Isoprene units are consecutively condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively), necessary for the biosynthesis of several metabolites. Polyprenyl transferases and synthases use polyprenyl pyrophosphates as their natural substrates; however, it is known that free polyprenols, such as farnesol (FOH), and geranylgeraniol (GGOH) can be incorporated into prenylated proteins, ubiquinone, cholesterol, and dolichols. Furthermore, FOH and GGOH have been shown to block the effects of isoprenoid biosynthesis inhibitors such as fosmidomycin, bisphosphonates, or statins in several organisms. This phenomenon is the consequence of a short pathway, which was observed for the first time more than 25 years ago: the polyprenol salvage pathway, which works via the phosphorylation of FOH and GGOH. Biochemical studies in bacteria, animals, and plants suggest that this pathway can be carried out by two enzymes: a polyprenol kinase and a polyprenyl-phosphate kinase. However, to date, only a few genes have been unequivocally identified to encode these enzymes in photosynthetic organisms. Nevertheless, pieces of evidence for the importance of this pathway abound in studies related to infectious diseases, cancer, dyslipidemias, and nutrition, and to the mitigation of the secondary effects of several drugs. Furthermore, nowadays it is known that both FOH and GGOH can be incorporated via dietary sources that produce various biological effects. This review presents, in a simplified but comprehensive manner, the most important data on the FOH and GGOH salvage pathway, stressing its biomedical importance The main objective of this review is to bring to light the need to discover and characterize the kinases associated with the isoprenoid salvage pathway in animals and pathogens.

Quorum sensing is a cell density-dependent microbial communication form, which can regulate several microbial properties, including virulence, biofilm formation and cell–cell competence. The phenomenon of fungal quorum sensing was first uncovered nearly 25 years ago, following the identification of farnesol and tyrosol as two key signalling molecules. Although the major roles of these regulatory molecules were elucidated, several questions primarily regarding tyrosol-mediated effects remain to be addressed, particularly with regard to molecular events influenced by tyrosol. Based on available literature data, tyrosol possesses potential antifungal activity, especially at supraphysiological concentrations. Moreover, its simultaneous usage with traditional antifungals shows potent synergistic activity against planktonic and sessile Candida cells, including both Candida albicans and certain non-albicans species. Currently, the deep molecular tyrosol-based investigations are still in their infancy compared with farnesol research. However, several promising findings were published in the past 10 years in terms of the potential usage of this compound as an alternative therapeutic treatment. Hence, this mini review summarizes the major functions of tyrosol as a signaling regulator compound in Candida morphogenesis. Furthermore, we discussed the most promising tyrosol-based in vitro data, which may be a foundation for the future development of in vivo models and ultimately innovative therapeutic strategies against fungal infections. Key points •  Tyrosol is a major quorum-sensing molecule in Candida species, promoting yeast-to-hyphae transition and biofilm formation •  Tyrosol has been shown to potentiate the efficacy of conventional antifungal agents, representing a promising adjunctive strategy for the treatment of fungal biofilms •  At supraphysiological concentrations, tyrosol induces oxidative stress, negatively influences the intracellular metal homeostasis and alters the fungal metabolism

Background Farnesol is a sesquiterpene from propolis and citrus fruit that shows promising anti-bacterial activity for caries treatment and prevention, but its hydrophobicity limits the clinical application. We aimed to develop the novel polymeric micelles (PMs) containing a kind of derivative of farnesol and a ligand of pyrophosphate (PPi) that mediated PMs to adhere tightly with the tooth enamel. Results Farnesal (Far) was derived from farnesol and successfully linked to PEG via an acid-labile hydrazone bond to form PEG-hyd-Far, which was then conjugated to PPi and loaded into PMs to form the aimed novel drug delivery system, PPi-Far-PMs. The in vitro test about the binding of PPi-Far-PMs to hydroxyapatite showed that PPi-Far-PMs could bind rapidly to hydroxyapatite and quickly release Far under the acidic conditions. Results from the mechanical testing and the micro-computed tomography indicated that PPi-Far-PMs could restore the microarchitecture of teeth with caries. Moreover, PPi-Far-PMs diminished the incidence and severity of smooth and sulcal surface caries in rats that were infected with Streptococcus mutans while being fed with a high-sucrose diet. The anti-caries efficacy of free Far can be improved significantly by PPi-Far-PMs through the effective binding of it with tooth enamel via PPi. Conclusions This novel drug-delivery system may be useful for the treatment and prevention of dental caries as well as the targeting therapy of anti-bacterial drugs in the oral disease.

Doxorubicin (DOXO) is an antineoplastic drug that is used extensively in managing multiple cancer types. However, DOXO-induced cardiotoxicity is a limiting factor for its widespread use and considerably affects patients’ quality of life. Farnesol (FSN) is a sesquiterpene with antioxidant, anti-inflammatory, and anti-tumor properties. Thus, the current study explored the cardioprotective effect of FSN against DOXO-induced cardiotoxicity. In this study, male Wistar rats were randomly divided into five groups (n = 7) and treated for 14 days. Group I (Control): normal saline, p.o. daily for 14 days; Group II (TOXIC): DOXO 2.4 mg/kg, i.p, thrice weekly for 14 days; Group III: FSN 100 mg/kg, p.o. daily for 14 days + DOXO similar to Group II; Group IV: FSN 200 mg/kg, p.o. daily for 14 days + DOXO similar to Group II; Group V (Standard): nifedipine 10 mg/kg, p.o. daily for 14 days + DOXO similar to Group II. At the end of the study, animals were weighed, blood was collected, and heart-weight was measured. The cardiac tissue was used to estimate biochemical markers and for histopathological studies. The observed results revealed that the FSN-treated group rats showed decrease in heart weight and heart weight/body weight ratio, reversed the oxidative stress, cardiac-specific injury markers, proinflammatory and proapoptotic markers and histopathological aberrations towards normal, and showed cardioprotection. In summary, the FSN reduces cardiac injuries caused by DOXO via its antioxidant, anti-inflammatory, and anti-apoptotic potential. However, more detailed mechanism-based studies are needed to bring this drug into clinical use.

When living in biological and interactive communities, microorganisms use quorum-sensing mechanisms for their communication. According to cell density, bacteria and fungi can produce signaling molecules (e.g., secondary metabolites), which participate, for example, in the regulation of gene expression and coordination of collective behavior in their natural niche. The existence of these secondary metabolites plays a main role in competence, colonization of host tissues and surfaces, morphogenesis, and biofilm development. Therefore, for the design of new antibacterials or antifungals and understanding on how these mechanisms occur, to inhibit the secretion of quorum-sensing (e.g., farnesol and tyrosol) molecules leading the progress of microbial infections seems to be an interesting option. In yeasts, farnesol has a main role in the morphological transition, inhibiting hyphae production in a concentration-dependent manner, while tyrosol has a contrary function, stimulating transition from spherical cells to germ tube form. It is beyond doubt that secretion of both molecules by fungi has not been fully described, but specific meaning for their existence has been found. This brief review summarizes the important function of these two compounds as signaling chemicals participating mainly in Candida morphogenesis and regulatory mechanisms.

Background and Objectives: Vulvovaginal candidiasis (VVC) is a mucous membrane infection, with an increased rate of antifungal resistance of Candida species. In this study, the in vitro efficacy of farnesol alone or in combination with traditional antifungals was assessed against resistant Candida strains recovered from women with VVC. Materials and Methods: Eighty Candida isolates were identified by multiplex polymerase chain reaction (PCR), and the antifungal susceptibility to amphotericin B (AMB), fluconazole (FLU), itraconazole (ITZ), voriconazole (VOR), clotrimazole (CTZ), and farnesol was tested by the standard microdilution method. The combinations of farnesol with each antifungal were calculated based on the fractional inhibitory concentration index (FICI). Result: Candida glabrata was the predominant species (48.75%) isolated from vaginal discharges, followed by C. albicans (43.75%), C. parapsilosis (3.75%), a mixed infection of C. albicans and C. glabrata (2.5%) and C. albicans and C. parapsilosis (1%). C. albicans and C. glabrata isolates had lower susceptibility to FLU (31.4% and 23.0%, respectively) and CTZ (37.1% and 33.3%, respectively). Importantly, there was “synergism” between farnesol–FLU and farnesol–ITZ against C. albicans and C. parapsilosis (FICI = 0.5 and 0.35, respectively), reverting the original azole-resistant profile. Conclusion: These findings indicate that farnesol can revert the resistance profile of azole by enhancing the activity of FLU and ITZ in resistant Candida isolates, which is a clinically promising result.