Assessing the antibacterial potential of 6-gingerol: Combined experimental and computational approaches.

The rise of antibiotic resistance in bacteria is becoming a global concern, particularly due to the dwindling supply of new antibiotics. This situation mandates the discovery of new antimicrobial candidates. Plant-derived natural compounds have historically played a crucial role in the development of antibiotics, serving as a rich source of substances possessing antimicrobial properties. Numerous studies have supported the reputation of 6-gingerol, a prominent compound found in the ginger family, for its antibacterial properties. In this study, the antibacterial activities of 6-gingerol were evaluated against Gram-negative bacteria, Acinetobacter baumannii and Klebsiella pneumoniae, with a particular focus on the clinically significant Gram-negative Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Furthermore, the anti-virulence activities were assessed in vitro, in vivo, and in silico. The current findings showed that 6-gingerol's antibacterial activity is due to its significant effect on the disruption of the bacterial cell membrane and efflux pumps, as it significantly decreased the efflux and disrupted the cell membrane of S. aureus and P. aeruginosa. Furthermore, 6-gingerol significantly decreased the biofilm formation and production of virulence factors in S. aureus and P. aeruginosa in concentrations below MICs. The anti-virulence properties of 6-gingerol could be attributed to its capacity to disrupt bacterial virulence-regulating systems; quorum sensing (QS). 6-Gingerol was found to interact with QS receptors and downregulate the genes responsible for QS. In addition, molecular docking, and molecular dynamics (MD) simulation results indicated that 6-gingerol showed a comparable binding affinity to the co-crystalized ligands of different P. aeruginosa QS targets as well as stable interactions during 100 ns MD simulations. These findings suggest that 6-gingerol holds promise as an anti-virulence agent that can be combined with antibiotics for the treatment of severe infections.

Relocating Glyceryl Trinitrate as an Anti-Virulence Agent against Pseudomonas aeruginosa and Serratia marcescens: Insights from Molecular and In Vivo Investigations.

The problem of antibiotic resistance is a global critical public health concern. In light of the threat of returning to the pre-antibiotic era, new alternative approaches are required such as quorum-sensing (QS) disruption and virulence inhibition, both of which apply no discernible selective pressure on bacteria, therefore mitigating the potential for the development of resistant strains. Bearing in mind the significant role of QS in orchestrating bacterial virulence, disrupting QS becomes essential for effectively diminishing bacterial virulence. This study aimed to assess the potential use of sub-inhibitory concentration (0.25 mg/mL) of glyceryl trinitrate (GTN) to inhibit virulence in Serratia marcescens and Pseudomonas aeruginosa. GTN could decrease the expression of virulence genes in both tested bacteria in a significant manner. Histopathological study revealed the ability of GTN to alleviate the congestion in hepatic and renal tissues of infected mice and to reduce bacterial and leukocyte infiltration. This study recommends the use of topical GTN to treat topical infection caused by P. aeruginosa and S. marcescens in combination with antibiotics.

Diminishing the Pathogenesis of the Food-Borne Pathogen Serratia marcescens by Low Doses of Sodium Citrate.

Protecting food from bacterial contamination is crucial for ensuring its safety and avoiding foodborne illness. Serratia marcescens is one of the food bacterial contaminants that can form biofilms and pigments that spoil the food product and could cause infections and illness to the consumer. Food preservation is essential to diminish such bacterial contaminants or at least reduce their pathogenesis; however, it should not affect food odor, taste, and consistency and must be safe. Sodium citrate is a well-known safe food additive and the current study aims to evaluate its anti-virulence and anti-biofilm activity at low concentrations against S. marcescens. The anti-virulence and antibiofilm activities of sodium citrate were evaluated phenotypically and genotypically. The results showed the significant effect of sodium citrate on decreasing the biofilm formation and other virulence factors, such as motility and the production of prodigiosin, protease, and hemolysins. This could be owed to its downregulating effect on the virulence-encoding genes. An in vivo investigation was conducted on mice and the histopathological examination of isolated tissues from the liver and kidney of mice confirmed the anti-virulence activity of sodium citrate. In addition, an in silico docking study was conducted to evaluate the sodium citrate binding ability to S. marcescens quorum sensing (QS) receptors that regulates its virulence. Sodium citrate showed a marked virtual ability to compete on QS proteins, which could explain sodium citrate's anti-virulence effect. In conclusion, sodium citrate is a safe food additive and can be used at low concentrations to prevent contamination and biofilm formation by S. marcescens and other bacteria.

Profiling the physiological pitfalls of anti-hepatitis C direct-acting agents in budding yeast.

Sofosbuvir and Daclatasvir are among the direct-acting antiviral (DAA) medications prescribed for the treatment of chronic hepatitis C (CHC) virus infection as combination therapy with other antiviral medications. DAA-based therapy achieves high cure rates, reaching up to 97% depending on the genotype of the causative hepatitis C virus (HCV). While DAAs have been approved as an efficient and well-tolerated therapy for CHC, emerging concerns about adverse cardiac side effects, higher risk of recurrence and occurrence of hepatocellular carcinoma (HCC) and doubts of genotoxicity have been reported. In our study, we investigated in detail physiological off-targets of DAAs and dissected the effects of these drugs on cellular organelles using budding yeast, a unicellular eukaryotic organism. DAAs were found to disturb the architecture of the endoplasmic reticulum (ER) and the mitochondria, while showing no apparent genotoxicity or DNA damaging effect. Our study provides evidence that DAAs are not associated with genotoxicity and highlights the necessity for adjunctive antioxidant therapy to mitigate the adverse effects of DAAs on ER and mitochondria.

Could the analgesic drugs, paracetamol and indomethacin, function as quorum sensing inhibitors?

The current failure of antimicrobials in treating life-threatening diseases, the high rate of multidrug resistant pathogens and the slow progress in the development of new antibiotics directed scientists to develop antivirulence drugs that targets quorum sensing (QS). In many microbes, QS acts as a communication system which control pathogenicity of microbes. Analgesics can be beneficial in controlling virulence traits of microbes and hence they may augment the efficacy of antimicrobials. In this study, two analgesics were screened for the inhibition of QS in Chromobacterium violaceum CV026 and their effects on virulence production in Pseudomonas aeruginosa PAO1 strain and clinical isolates of Acinetobacter baumannii were evaluated. The traits investigated were biofilm formation, pyocyanin and rhamnolipid production, twitching, swarming or surface associated motilities, production of protease, phospholipase and gelatinase enzymes and sensitivity to oxidative stress. Relative expression of abaI gene was calculated by performing qRT-PCR. Docking analysis of paracetamol as QSI (quorum sensing inhibitor) of AbaI and AbaR proteins was performed. Paracetamol inhibited QS in CV026, but indomethacin devoids anti-QS activity. Paracetamol inhibited virulence factors of PAO1. It strongly inhibited biofilm formation, and swarming by 66.4% and 57.1%, respectively. While, it moderately to slightly inhibited rhamnolipid, pyocyanin, gelatinase, resistance to oxidative stress, protease and twitching motility by 33.3%, 33.1% 17.5%, 9.1%, 8.7% and 7.7%, respectively. For A. baumannii, paracetamol strongly inhibited biofilm by 39.7-93% and phospholipase enzyme by 8.7-100%, reduced twitching and surface motility by 6.7-82.5% and 7.7-29.4%, respectively, And slightly reduced sensitivity to oxidative stress by 3.3-36.4%. Paracetamol at sub-MIC suppressed the expression of abaI gene by 32% in A. baumannii. Docking studies suggested that paracetamol can bind to AbaR and AbaI proteins and bind more to AbaR, hence it may act by inhibiting AHL signal reception. As a conclusion, paracetamol, beside its analgesic activity, has anti-QS activity and could be used in the eradication of P. aeruginosa and A. baumannii infections in combination with antibiotics.

Drugs with new lease of life as quorum sensing inhibitors: for combating MDR Acinetobacter baumannii infections.

The emergence of multidrug-resistant (MDR) strains is a major health problem worldwide. There is an urgent need for novel strategies to combat bacterial infections caused by MDR strains like Pseudomonas aeruginosa and Acinetobacter baumannii. Quorum sensing (QS) is a critical communication system in bacterial community controlling survival and virulence. The awareness of the importance of QS in bacterial infections has stimulated research to identify QS inhibitors (QSIs) to defeat microbes. In this study, four FDA-approved drugs (besides azithromycin as positive QSI) were tested for potential QS inhibition against clinical A. baumannii isolates and P. aeruginosa (PAO1) standard strain. The inhibitory effect of these drugs on virulence factors of both microbes has been investigated. The studied virulence factors include biofilm formation, twitching and swarming motilities, proteolytic enzyme production, and resistance to oxidative stress. The four tested drugs (erythromycin, levamisole, chloroquine, and propranolol) inhibited QS in Chromobacterium violaceum by 84, 72, 55.1, and 37.3%, respectively. They also significantly inhibited virulence factors in both PAO1 and A. baumannii at sub-inhibitory concentrations. These findings were confirmed by qRT-PCR and mice mortality test, where tested drugs highly repressed the expression of abaI gene and showed significantly improved mice survival rates. In addition, molecular docking studies against AbaI and AbaR proteins of QS system in A. baumannii revealed the potential inhibition of QS by tested drugs. Beside their known activities, the tested drugs could be given new life as QSIs to combat A. baumannii nosocomial infections (alone or in combination with antimicrobials).