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Abstract Resistance to antibiotics is a critical growing public health problem that desires urgent action to combat. To avoid the stress on bacterial growth that evokes the resistance development, anti-virulence agents can be an attractive strategy as they do not target bacterial growth. Quorum sensing (QS) systems play main roles in controlling the production of diverse virulence factors and biofilm formation in bacteria. Thus, interfering with QS systems could result in mitigation of the bacterial virulence. Cilostazol is an antiplatelet and a vasodilator FDA approved drug. This study aimed to evaluate the anti-virulence activities of cilostazol in the light of its possible interference with QS systems in Pseudomonas aeruginosa. Additionally, the study examines cilostazol’s impact on the bacterium’s ability to induce infection in vivo, using sub-inhibitory concentrations to minimize the risk of resistance development. In this context, the biofilm formation, the production of virulence factors and influence on the in vivo ability to induce infection were assessed in the presence of cilostazol at sub-inhibitory concentration. Furthermore, the outcome of combination with antibiotics was evaluated. Cilostazol interfered with biofilm formation in P. aeruginosa. Moreover, swarming motility, biofilm formation and production of virulence factors were significantly diminished. Histopathological investigation revealed that liver, spleen and kidney tissues damage was abolished in mice injected with cilostazol-treated bacteria. Cilostazol exhibited a synergistic outcome when used in combination with antibiotics. At the molecular level, cilostazol downregulated the QS genes and showed considerable affinity to QS receptors. In conclusion, Cilostazol could be used as adjunct therapy with antibiotics for treating Pseudomonal infections. This research highlights cilostazol’s potential to combat bacterial infections by targeting virulence mechanisms, reducing the risk of antibiotic resistance, and enhancing treatment efficacy against P. aeruginosa. These findings open avenues for repurposing existing drugs, offering new, safer, and more effective infection control strategies.

Abstract Background Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC). Objectives This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in C. albicans resistant isolates and the potential use of Fusidic acid in combination with fluconazole to potentiate the antifungal activity of fluconazole to restore its activity in the resistant C. albicans isolates. Methods The resistance of C. albicans isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis. Results Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in C. albicans cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue. Conclusion The current findings highlight FA’s potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis.

Pseudomonas aeruginosa belongs to the critical pathogens that represent a global public health problem due to their high rate of resistance as listed by WHO. P. aeruginosa can result in many nosocomial infections especially in individuals with compromised immune systems. Attenuating virulence factors by interference with quorum sensing (QS) systems is a promising approach to treat P. aeruginosa-resistant infections. Thymoquinone is a natural compound isolated from Nigella sativa (black seed) essential oil. In this study, the minimum inhibitory concentration of thymoquinone was detected followed by investigating the antibiofilm and antivirulence activities of the subinhibitory concentration of thymoquinone against P. aeruginosa PAO1. The effect of thymoquinone on the expression of QS genes was assessed by quantitative real-time PCR, and the protective effect of thymoquinone against the pathogenesis of PAO1 in mice was detected by the mouse survival test. Thymoquinone significantly inhibited biofilm, pyocyanin, protease activity, and swarming motility. At the molecular level, thymoquinone markedly downregulated QS genes lasI, lasR, rhlI, and rhlR. Moreover, thymoquinone could protect mice from the pathologic effects of P. aeruginosa increasing mouse survival from 20% to 100%. In conclusion, thymoquinone is a promising natural agent that can be used as an adjunct therapeutic agent with antibiotics to attenuate the pathogenicity of P. aeruginosa.

The development of resistance to carbapenems in Klebsiella pneumoniae due to the production of metallo-β-lactamases (MBLs) is a critical public health problem because carbapenems are the last-resort drugs used for treating severe infections of extended-spectrum β-lactamases (ESBLs) producing K. pneumoniae. Restoring the activity of carbapenems by the inhibition of metallo-β-lactamases is a valuable approach to combat carbapenem resistance. In this study, two well-characterized clinical multidrug and carbapenem-resistant K. pneumoniae isolates were used. The sub-inhibitory concentrations of pantoprazole and the well-reported metallo-β-lactamase inhibitor captopril inhibited the hydrolytic activities of metallo-β-lactamases, with pantoprazole having more inhibiting activities. Both drugs, when used in combination with meropenem, exhibited synergistic activities. Pantoprazole could also downregulate the expression of the metallo-β-lactamase genes blaNDM and blaVIM. A docking study revealed that pantoprazole could bind to and chelate zinc ions of New Delhi and Verona integron-encoded MBL (VIM) enzymes with higher affinity than the control drug captopril and with comparable affinity to the natural ligand meropenem, indicating the significant inhibitory activity of pantoprazole against metallo-β-lactamases. In conclusion, pantoprazole can be used in combination with meropenem as a new strategy for treating serious infections caused by metallo-β-lactamases producing K. pneumoniae.

Abstract Introduction The emergence of multidrug-resistant Klebsiella pneumoniae in hospitals represents a serious threat to public health. Infections caused by Klebsiella pneumoniae are widespread in healthcare institutions, mainly pneumonia, bloodstream infections, and infections affecting neonates in intensive care units; so, it is necessary to combat this pathogen with new strategies. Targeting virulence factors necessary to induce host damage and disease is a new paradigm for antimicrobial therapy with several potential benefits that could lead to decreased resistance. Background The influence of metformin, N-acetylcysteine, and secnidazole on Klebsiella pneumoniae virulence factors production was tested. The production of Klebsiella pneumoniae virulence factors such as biofilm formation, urease, proteases, hemolysins, and tolerance to oxidative stress was evaluated phenotypically using sub-inhibitory concentration (1/8 MIC) of metformin, N-acetylcysteine, and secnidazole. For more confirmation, qRT-PCR was used to assess the relative expression level of rmpA, wcaG, fimH-1, mrkD, ureA, and khe genes regulating virulence factors production. Results Metformin, N-acetylcysteine, and secnidazole were all found to have a powerful inhibitory effect on the production of virulence factors phenotypically. Our results showed a significant reduction in the expression level of rmpA, wcaG, fimH-1, mrkD, ureA, and khe genes. Furthermore, the tested drugs were investigated in vivo to inform their ability to protect mice against Klebsiella pneumoniae pathogenesis. Conclusions Metformin, N-acetylcysteine, and secnidazole inhibited the virulence of Klebsiella pneumoniae. Besides combating resistant Klebsiella pneumoniae, the tested drugs could also serve as an adjuvant to traditional antibiotics.

Abstract Background Infections affecting neonates caused by Staphylococcus aureus are widespread in healthcare facilities; hence, novel strategies are needed to fight this pathogen. In this study, we aimed to investigate the effectiveness of the FDA-approved medications ascorbic acid, dexamethasone, and sodium bicarbonate to reduce the virulence of the resistant Staphylococcus aureus bacteria that causes neonatal sepsis and seek out suitable alternatives to the problem of multi-drug resistance. Methods Tested drugs were assessed phenotypically and genotypically for their effects on virulence factors and virulence-encoding genes in Staphylococcus aureus. Furthermore, drugs were tested in vivo for their ability to reduce Staphylococcus aureus pathogenesis. Results Sub-inhibitory concentrations (1/8 MIC) of ascorbic acid, dexamethasone, and sodium bicarbonate reduced the production of Staphylococcus aureus virulence factors, including biofilm formation, staphyloxanthin, proteases, and hemolysin production, as well as resistance to oxidative stress. At the molecular level, qRT-PCR was used to assess the relative expression levels of crtM, sigB, sarA, agrA, hla, fnbA, and icaA genes regulating virulence factors production and showed a significant reduction in the relative expression levels of all the tested genes. Conclusions The current findings reveal that ascorbic acid, dexamethasone, and sodium bicarbonate have strong anti-virulence effects against Staphylococcus aureus. Thus, suggesting that they might be used as adjuvants to treat infections caused by Staphylococcus aureus in combination with conventional antimicrobials or as alternative therapies.

Key points A new formation of silver metformin nanostructure. The in vitro inhibition of S. aureus virulence factors. Nano structure form improves the activity of anti-virulence agents.

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.

The repurposing of drugs is one of the most competent strategies for discovering new antimicrobial agents. Vildagliptin is a dipeptidyl peptidase-4 inhibitor (DPI-4) that is used effectively in combination with metformin to control blood glucose levels in diabetic patients. This study was designed to evaluate the anti-virulence activities of this combination against one of the most clinically important pathogens, Pseudomonas aeruginosa. The current findings show a significant ability of the vildagliptin–metformin combination to diminish biofilm formation, bacterial motility, and the production of virulent extracellular enzymes and pyocyanin pigment. Furthermore, this drug combination significantly increased the susceptibility of P. aeruginosa to oxidative stress, indicating immunity enhancement in the eradication of bacterial cells. In compliance with the in vitro findings, the histopathological photomicrographs of mice showed a considerable protective effect of the metformin–vildagliptin combination against P. aeruginosa, revealing relief of inflammation due to P. aeruginosa-induced pathogenesis. P. aeruginosa mainly employs quorum sensing (QS) systems to control the production of its huge arsenal of virulence factors. The anti-virulence activities of the metformin–vildagliptin combination can be interrupted by the anti-QS activities of both metformin and vildagliptin, as both exhibited a considerable affinity to QS receptors. Additionally, the metformin–vildagliptin combination significantly downregulated the expression of the main three QS-encoding genes in P. aeruginosa. These findings show the significant anti-virulence activities of metformin–vildagliptin at very low concentrations (10, 1.25 mg/mL, respectively) compared to the concentrations (850, 50 mg/mL, respectively) used to control diabetes.

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.

Bacteria communicate with each other using quorum sensing (QS) which works in an inducer/receptor manner. QS plays the main role in orchestrating diverse bacterial virulence factors. Pseudomonas aeruginosa is one of the most clinically important bacterial pathogens that can cause infection in almost all body tissues. Besides its efficient capability to develop resistance to different antibiotics, P. aeruginosa acquires a huge arsenal of virulence factors that are controlled mainly by QS. Challenging QS with FDA-approved drugs and natural products was proposed as a promising approach to mitigate bacterial virulence enabling the host immunity to complete the eradication of bacterial infection. The present study aims to evaluate the dipeptidase inhibitor-4 inhibitor hypoglycemic linagliptin anti-QS and anti-virulence activities against P. aeruginosa in vitro, in vivo, and in silico. The current results revealed the significant ability to diminish the production of protease and pyocyanin, motility, and biofilm formation in P. aeruginosa. Furthermore, the histopathological examination of liver and kidney tissues of mice injected with linagliptin-treated bacteria showed an obvious reduction of pathogenesis. Linagliptin downregulation to QS-encoding genes, besides the virtual ability to interact with QS receptors, indicates its anti-QS activities. In conclusion, linagliptin is a promising anti-virulence and anti-QS candidate that can be used solely or in combination with traditional antimicrobial agents in the treatment of P. aeruginosa aggressive infections.

The emergence of resistant microbes threatens public health on our planet, and the emergence of resistant bacteria against the most commonly used antibiotics necessitates urgent alternative therapeutic options. One way to fight resistant microbes is to design new antimicrobial agents, however, this approach takes decades of research. An alternative or parallel approach is to target the virulence of bacteria with natural or synthetic agents. Active constituents from medicinal plants represent a wide library to screen for natural anti-virulence agents. Caraway is used as a traditional spice and in some medicinal applications such as carminative, antispasmodic, appetizer, and expectorant. Caraway essential oil is rich in terpenes that were previously reported to have antimicrobial activities. In our study, we tested the caraway essential oil in sub-inhibitory concentration as a virulence agent against the Gram-negative bacteria Pseudomonas aeruginosa. Caraway essential oil in sub-inhibitory concentration dramatically blocked protease activity, pyocyanin production, biofilm formation, and quorum sensing activity of P. aeruginosa. The gas chromatography–mass spectroscopy (GC-MS) profile of caraway fruit oil identified 13 compounds representing 85.4% of the total oil components with carvone and sylvestrene as the main constituents. In conclusion, caraway essential oil is a promising virulence-attenuating agent that can be used against topical infections caused by P. aeruginosa.

The development of bacterial resistance to traditional antibiotics constitutes an emerging public health issue. Promising approaches have been innovated to conquer bacterial resistance, and targeting bacterial virulence is one of these approaches. Bacterial virulence mitigation offers several merits, as antivirulence agents do not affect the growth of bacteria and hence do not induce bacteria to develop resistance. In this direction, numerous drugs have been repurposed as antivirulence agents prior to their clinical use alone or in combination with traditional antibiotics. Quorum sensing (QS) plays a key role in controlling bacterial virulence. In the current study, dipeptidase inhibitor-4 (DPI-4) antidiabetic gliptins were screened for their antivirulence and anti-quorum sensing (anti-QS) activities against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus. Upon assessing their antibiofilm activities, the ten tested gliptins significantly diminished biofilm formation. In particular, sitagliptin exhibited the most efficient antibiofilm activity, so it was chosen as a representative of all gliptins to further investigate its antivirulence activity. Sitagliptin significantly protected mice from P. aeruginosa and S. aureus pathogenesis. Furthermore, sitagliptin downregulated QS-encoding genes in P. aeruginosa and S. aureus. To test the anti-QS activities of gliptins, a detailed molecular docking study was conducted to evaluate the gliptins’ binding affinities to P. aeruginosa and S. aureus QS receptors, which helped explain the anti-QS activities of gliptins, particularly sitagliptin and omarigliptin. In conclusion, this study evaluates the possible antivirulence and anti-QS activities of gliptins that could be promising novel candidates for the treatment of aggressive Gram-negative or -positive bacterial infections either alone or as adjuvants to other antibiotics.

The development of bacterial resistance is an insistent global health care issue, especially in light of the dwindled supply of new antimicrobial agents. This mandates the development of new innovative approaches to overcome the resistance development obstacle. Mitigation of bacterial virulence is an interesting approach that offers multiple advantages. Employing safe chemicals or drugs to mitigate bacterial virulence is an additive advantage. In the current study, the in vitro antivirulence activities of citrate were evaluated. Significantly, sodium citrate inhibited bacterial biofilm formation at sub-MIC concentrations. Furthermore, sodium citrate decreased the production of virulence factors protease and pyocyanin and diminished bacterial motility. Quorum sensing (QS) is the communicative system that bacterial cells utilize to communicate with each other and regulate the virulence of the host cells. In the present study, citrate in silico blocked the Pseudomonas QS receptors and downregulated the expression of QS-encoding genes. In conclusion, sodium citrate showed a significant ability to diminish bacterial virulence in vitro and interfered with QS; it could serve as a safe adjuvant to traditional antibiotic treatment for aggressive resistant bacterial infections such as Pseudomonas aeruginosa infections.

Hepatitis C virus (HCV) is one of the most epidemic viral infections in the world. Three-quarters of individuals infected with HCV become chronic. As a consequence of persistent inflammation, a considerable percentage of chronic patients progress to liver fibrosis, cirrhosis, and finally hepatocellular carcinoma. Cytokines, which are particularly produced from T-helper cells, play a crucial role in immune protection against HCV and the progression of the disease as well. In this study, the role of interleukins IL-33, IL-17, and IL-25 in HCV patients and progression of disease from chronicity to hepatocellular carcinoma will be characterized in order to use them as biomarkers of disease progression. The serum levels of the tested interleukins were measured in patients suffering from chronic hepatitis C (CHC), hepatocellular carcinoma (HCC), and healthy controls (C), and their levels were correlated to the degree of liver fibrosis, liver fibrosis markers and viral load. In contrast to the IL-25 serum level, which increased in patients suffering from HCC only, the serum levels of both IL-33 and IL-17 increased significantly in those patients suffering from CHC and HCC. In addition, IL-33 serum level was found to increase by liver fibrosis progression and viral load, in contrast to both IL-17 and IL-25. Current results indicate a significant role of IL-33 in liver inflammation and fibrosis progress in CHC, whereas IL-17 and IL-25 may be used as biomarkers for the development of hepatocellular carcinoma.

Pseudomonas aeruginosa can cause a variety of healthcare-associated infections by its arsenal of virulence factors. Virulence factor production is largely controlled by the cell-to-cell communication system termed quorum sensing (QS). Targeting QS may be a good approach to inhibit the production of virulence factors and attenuate pathogenicity without exerting selective stress on bacterial growth. This will greatly reduce the emergence of resistant mutants. In this work, we investigated the anti-virulence and anti-QS activities of the FDA-approved drug allopurinol against the P. aeruginosa PAO1 strain. Allopurinol at 200 µg/mL (1/10 MIC) significantly decreased the production of the QS-controlled Chromobacterium violaceum CV026 violet pigment violacein and other P. aeruginosa QS-controlled virulence factors phenotypically. Furthermore, allopurinol reduced the infiltration of P. aeruginosa and leucocytes and diminished the congestion in the liver and kidney tissues of infected mice. In silico study showed that allopurinol could compete with the autoinducers on binding to the receptors LasR and RhlR by hydrogen bonding. On the molecular level, qRT-PCR proved that allopurinol showed a significant downregulating effect on all tested QS-encoding genes that regulate virulence factor production. In summary, allopurinol is a promising QS inhibitor that may be useful in the future treatment of P. aeruginosa infection.

Serratia marcescens is an opportunistic pathogen that causes diverse nosocomial infections. S. marcescens has developed considerable resistance to different antibiotics and is equipped with an armory of virulence factors. These virulence factors are regulated in S. marcescens by an intercellular communication system termed quorum sensing (QS). Targeting bacterial virulence and QS is an interesting approach to mitigating bacterial pathogenesis and overcoming the development of resistance to antimicrobials. In this study, we aimed to evaluate the anti-virulence activities of secnidazole on a clinical isolate of S. marcescens. The effects of secnidazole at sub-inhibitory concentrations (sub-MICs) on virulence factors, swarming motility, biofilm formation, proteases, hemolysin activity, and prodigiosin production were evaluated in vitro. Secnidazole’s protective activity against S. marcescens pathogenesis was assessed in vivo in mice. Furthermore, a molecular docking study was conducted to evaluate the binding ability of secnidazole to the S. marcescens SmaR QS receptor. Our findings showed that secnidazole at sub-MICs significantly reduced S. marcescens virulence factor production in vitro and diminished its pathogenesis in mice. The insilico docking study revealed a great ability of secnidazole to competitively hinder the binding of the autoinducer to the SmaR QS receptor. In conclusion, secnidazole is a promising anti-virulence agent that may be used to control infections caused by S. marcescens.

The bacterial resistance development due to the incessant administration of antibiotics has led to difficulty in their treatment. Natural adjuvant compounds can be co-administered to hinder the pathogenesis of resistant bacteria. Sotolon is the prevailing aromatic compound that gives fenugreek its typical smell. In the current work, the anti-virulence activities of sotolon on Pseudomonas aeruginosa have been evaluated. P. aeruginosa has been treated with sotolon at sub-minimum inhibitory concentration (MIC), and production of biofilm and other virulence factors were assessed. Moreover, the anti-quorum sensing (QS) activity of sotolon was in-silico evaluated by evaluating the affinity of sotolon to bind to QS receptors, and the expression of QS genes was measured in the presence of sotolon sub-MIC. Furthermore, the sotolon in-vivo capability to protect mice against P. aeruginosa was assessed. Significantly, sotolon decreased the production of bacterial biofilm and virulence factors, the expression of QS genes, and protected mice from P. aeruginosa. Conclusively, the plant natural substance sotolon attenuated the pathogenicity of P. aeruginosa, locating it as a plausible potential therapeutic agent for the treatment of its infections. Sotolon can be used in the treatment of bacterial infections as an alternative or adjuvant to antibiotics to combat their high resistance to antibiotics.

Diabetic foot ulcers are recognized to be a severe complication of diabetes, increasing the risk of amputation and death. The bacterial infection of Diabetic foot ulcers with virulent and resistant bacteria as Proteus mirabilis greatly worsens the wound and may not be treated with conventional therapeutics. Developing new approaches to target bacterial virulence can be helpful to conquer such infections. In the current work, we evaluated the anti-virulence activities of the widely used antibacterial metronidazole. The minimum inhibitory concentrations (MIC) and minimum biofilm eradication concentrations (MEBC) were determined for selected antibiotics which P. mirabilis was resistant to them in the presence and absence of metronidazole in sub-MIC. The effect of metronidazole in sub-MIC on P. mirabilis virulence factors as production of exoenzymes, motilities, adhesion and biofilm formation, were evaluated. Furthermore, molecular docking of metronidazole into P. mirabilis adhesion and essential quorum sensing (QS) proteins, was performed. The results revealed a significant ability of metronidazole to in-vitro inhibit P. mirabilis virulence factors and antagonize its essential proteins. Moreover, metronidazole markedly decreased the MICs and MBECs of tested antibiotics. Conclusively, metronidazole in sub-MIC is a plausible anti-virulence and anti-QS agent that can be combined to other antibiotics as anti-virulence adjuvant to defeat aggressive infections.

Serratia marcescens is an opportunistic nosocomial pathogen and causes wound and burn infections. It shows high resistance to antibiotics and its pathogenicity is mediated by an arsenal of virulence factors. Another therapeutic option to such infections is targeting quorum sensing (QS), which controls the expression of different S. marcescens virulence factors. Prevention of QS can deprive S. marcescens from its bacterial virulence without applying stress on the bacterial growth and facilitates the eradication of the bacteria by immunity. The objective of the current study is to explore the antimicrobial and antivirulence activities of xylitol against S. marcescens. Xylitol could inhibit the growth of S. marcescens. Sub-inhibitory concentrations of xylitol could inhibit biofilm formation, reduce prodigiosin production, and completely block protease activity. Moreover, xylitol decreased swimming motility, swarming motility and increased the sensitivity to hydrogen peroxide. The expression of rsmA, pigP, flhC, flhD fimA, fimC, shlA bsmB, and rssB genes that regulate virulence factor production was significantly downregulated by xylitol. In silico study showed that xylitol could bind with the SmaR receptor by hydrophobic interaction and hydrogen bonding, and interfere with the binding of the natural ligand with SmaR receptor. An in vivo mice survival test confirmed the ability of xylitol to protect mice against the virulence of S. marcescens. In conclusion, xylitol is a growth and virulence inhibitor in S. marcescens and can be employed for the treatment of S. marcescens wound and burn infections.

Bacterial resistance represents one of the emerging obstacles in plants, animals, and humans that impairs treatment with antibacterial agents. Targeting of the bacterial quorum sensing system is one of the strategies to overcome this problem. Recently, research has been focused on natural and food components which can function as quorum sensing inhibitors. In this study, a methanol extract from Salix tetrasperma stem bark was phytochemically profiled by LC-MS analysis. This resulted in the identification of 38 secondary metabolites with (epi)catechin-(epi)catechin, epicatechin, tremulacin, salicortin, and trichocarposide as the major constituents. The extracts of both stem bark and the previously profiled flower of S. tetrasperma were tested for anti-quorum sensing activity in a common and widely distributed pathogen Pseudomonas aeruginosa. The natural products inhibited swimming and swarming motilities, as well as proteolytic and hemolytic activities in a dose-dependent manner. Molecular docking of the constituents from both extracts against the quorum sensing controlling systems Lasl/LasR, rhll/rhlR, and PQS/MvfR showed that epicatechin, (epi)catechin-(epi)catechin, p-hydroxy benzoyl galloyl glucose, p-hydroxy benzoyl protocatechuic acid glucose, and caffeoylmalic acid could be the main active components. This study supports the importance of secondary metabolites, especially polyphenols, as quorum sensing inhibitors.

Lead-trihalide perovskite solar cells are an important photovoltaic technology. We investigate the effect of light induced degradation on perovskite solar cells. During exposure, the open-circuit voltage (Voc) of the device increases, whereas the short-circuit current (Isc) shows a decrease. The degradation can be completely recovered using thermal annealing in dark. We develop a model based on light induced generation of ions and migration of these ions inside the material to explain the changes in Isc, Voc, capacitance and dark current upon light exposure and post-exposure recovery. There was no change in defect density in the material upon exposure.

Photovoltaic devices with perovskite materials as light absorbing material were fabricated through sequential vapor deposition of lead iodide and methylammonium iodide with undoped poly3hexylthiophene (P3HT) as a hole transporting layer. The sequential vapor deposition process produced films and devices with the large grains and low defect densities, very small values of dark current, and high open circuit voltages. The thickness of the P3HT layer was a critical parameter for achieving high solar conversion efficiencies of 13.7%. The vapor deposition process also produced devices with a tight distribution of performance characteristics and very high open circuit voltages (0.99 V).

BACKGROUND:Serratia marcescens is an emerging pathogen that causes a variety of health care associated infections. S. marcescens is equipped with an arsenal of virulence factors such as biofilm formation, swimming and swarming motilities, prodigiosin, protease and others which enable it to initiate and cause the infection. These virulence factors are orchestrated under the umbrella of an intercellular communication system named Quorum sensing (QS). QS allows bacterial population to synchronize the expression of virulence genes upon detection of a chemical signaling molecule. Targeting bacterial virulence is a promising approach to attenuate bacteria and enhances the ability of immune system to eradicate the bacterial infection. Drug repurposing is an advantageous strategy that confers new applications for drugs outside the scope of their original medical use. This promising strategy offers the use of safe approved compounds, which potentially lowers the costs and shortens the time than that needed for development of new drugs. Sitagliptin is dipeptidyl peptidase-4 (DPP-4) inhibitor, is used to treat diabetes mellitus type II as it increases the production of insulin and decreasing the production of glucagon by the pancreas. We aimed in this study to repurpose sitagliptin, investigating the anti-virulence activities of sitagliptin on S. marcescens. METHODS:The effect of sub-inhibitory concentrations of sitagliptin on virulence factors; protease, prodigiosin, biofilm formation, swimming and swarming motilities was estimated phenotypically. The qRT-PCR was used to show the effect of sitagliptin on the expression of QS-regulated virulence genes. The in-vivo protective activity of sitagliptin on S. marcescens pathogenesis was evaluated on mice. RESULTS:Sitagliptin (1 mg/ml) significantly reduced the biofilm formation, swimming and swarming motilities, prodigiosin and protease. The qRT-PCR confirmed the effect on virulence as shown by down regulating the expression of fimA, fimC, flhC, flhD, bsmB, rssB, rsmA, pigP, and shlA genes. Moreover, the in-vivo findings showed the efficient ability of sitagliptin to weaken S. marcescens pathogenesis. CONCLUSION:Sitagliptin is a promising anti-virulence agent against S. marcescens that may be beneficial in the control of healthcare associated infections caused by S. marcescens.

The incidence of mechanical complications related to myocardial infarction has decreased due to various factors over the last few decades. Patients admitted for acute ST segment elevation myocardial infarction (STEMI) may respond well to thrombolytic therapy before being taken up for coronary angiography and percutaneous coronary intervention depending on the facilities available at the specific center. Unfortunately, some patients develop complications of myocardial infarction during hospital stay or postdischarge. We present a patient admitted with acute STEMI responding well to thrombolytic therapy. During transthoracic echocardiography of the patient in Intensive Care Unit, the patient developed ventricular septal rupture, right ventricular free wall rupture, hemopericardium, cardiac tamponade, and cardiogenic shock and expired.