Fruit Extract and Phenolic Compounds of Phyllanthus emblica Fruits as Bioactivity Enhancer of Chloramphenicol Against Bacterial Species.

Phyllanthus emblica L. (syn. Emblica officinalis) fruits have been traditionally exploited to enhance the immune system and provide protection against bacterial and fungal diseases. The present study aimed to evaluate the synergistic interactions between chloramphenicol and several phenolic compounds found in P. emblica fruits against bacterial strains. The combination of P. emblica fruit extracts and its phenolic compounds demonstrated synergistic antibacterial activity when used in conjunction with chloramphenicol against both Gram-positive and Gram-negative bacteria. The combination of MICGA with ½MICChl exhibited a significant increase in bioactivity, with a 333.33-fold enhancement against B. subtilis. Similarly, the combination of MICGA with 2MICChl displayed a bioactivity enhancement of 16.02 folds against S. aureus. The co-administration of ½MICQ and ½MICChl resulted in a significant 35.71-fold increase in bioactivity against P. aeruginosa. Similarly, the combination of MIC GA and ½MICChl exhibited a remarkable 166.66-fold enhancement in bioactivity against E. coli. The combinations of 2MICFPE and ½MICChloramphenicol, as well as ½MICGA and ½MICChl demonstrated the highest bioactivity enhancement of 17.85 folds for K. pneumoniae. This study claimed that the fruit extracts of P. emblica and its phenolic compounds could be utilized to augment the effectiveness of conventional antibiotics, which have acquired resistance to bacterial infections.

Synergistic Effect of Essential Oils and Antifungal Agents in Fighting Resistant Clinical Isolates of Candida auris.

Recently, a large number of nosocomial infections have been caused by an emerging pathogen that is rising as a worldwide issue in human health: Candida auris. This yeast is considered resistant to antifungals of the first-line therapies, and consequently it is related to morbidity and mortality. Therefore, the aim of this research was to determine the in vitro anti-C. auris activity against twenty-three resistant clinical strains of different essential oils (EOs), pure or in combination with traditional antifungal agents, mainly caspofungin, fluconazole, micafungin and 5-flucytosine. Broth dilution assay was performed to evaluate the fungistatic and fungicidal effectiveness of fifteen EOs towards all the C. auris isolates. The data demonstrated that EOs were able to prevent C. auris growth, with MIC values ranging from 0.03 to 1% for the efficacious EOs (thyme, cinnamon, geranium, clove bud, lemongrass and mentha of Pancalieri), whereas the MICs were >1% for the ineffective ones. Thereafter, the six most effective EOs were used to perform the checkerboard experiments by assaying simultaneously the activity of EOs and traditional antifungals towards two selected strains. The most promising synergic combinations towards C. auris, depending on the isolate, were those with micafungin and geranium, thyme, cinnamon, lemongrass or clove bud EOs, with fluconazole and mentha of Pancalieri EO, and with 5-flucytosine and mentha of Pancalieri EO. These EOs and their combinations with antifungal drugs may provide a useful therapeutic alternative that could reduce the dose of the individual components, limiting the overall side effects. These associations might be a prospective option for the future treatment of infections, thus helping to overcome the challenging issue of resistance in C. auris.

Naringenin-Zinc Oxide Nanocomposites Amalgamated Polymeric Gel Augmented Drug Delivery and Attenuated Experimental Cutaneous Candidiasis in Balb/c Mice: In Vitro and In Vivo Studies.

Naringenin (NRG) inhibits the fungal 17ß-hydroxysteroid dehydrogenase accountable for ergosterol synthesis in Candida albicans (C. albicans), a causative agent for cutaneous candidiasis. In present research, NRG was complexed with ZnO nanomaterial (NRG-Zn2+) to synthesize NRG-Zn2+ nanocomposites. The particle size and ζ-potential of NRG-Zn2+ nanocomposites were respectively estimated to be 180.33 ± 1.22-nm and - 3.92 ± 0.35-mV. In silico data predicted the greater affinity of NRG-Zn2+ nanocomposite for 14α-demethylase and ceramide in comparison to NRG alone. Later, NRG-Zn2+ nanocomposites solution was transformed in to naringenin-zinc oxide nanocomposites loaded chitosan gel (NRG-Zn-CS-Gel) with viscosity and firmness of 854806.7 ± 52386.43 cP and 698.27 ± 10.35 g, respectively. The ex-vivo skin permeation demonstrated 70.49 ± 5.22% skin retention, significantly greater (P < 0.05) than 44.48 ± 3.06% of naringenin loaded chitosan gel (NRG-CS-Gel) and 31.24 ± 3.28% of naringenin solution (NRG Solution). NRG-Zn-CS-Gel demonstrated 6.71 ± 0.84% permeation of NRG with a flux value of 0.046 ± 0.01-µg/cm2/h. The MIC50 of NRG-Zn-CS-Gel against C. albicans was estimated to be 0.156-µg/mL with FICI (fractional inhibitory concentration index) of 0.018 that consequently exhibited synergistic efficacy. Further, NRG-Zn-CS-Gel demonstrated superior antifungal efficacy in C. albicans induced cutaneous candidiasis infection in Balb/c mice. The fungal burden in NRG-Zn-CS-Gel treated group was 109 ± 25 CFU/mL, significantly lower (P < 0.05) than positive control (2260 ± 446 CFU/mL), naringenin loaded chitosan gel (NRG-CS-Gel; 928 ± 127 CFU/mL) and chitosan gel (CS-Gel; 2116 ± 186 CFU/mL) treated mice. Further, histopathology examination and cytokine profiling of TNF-α, IL-1ß and IL-10 revealed the healing of skin and inflammation associated with cutaneous candidiasis infection. In conclusion, NRG-Zn-CS-Gel may be a potential candidate for translating in to a clinical viable topical nanotherapeutic.

Laurocapram, a transdermal enhancer, boosts cephalosporin's antibacterial activity against Methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA), a notorious bacterium with high drug resistance and easy recurrence after surgery, has posed significant clinical treatment challenges. In the current scarcity of new antibiotics, the identification of adjuvants to existing antibiotics is a promising approach to combat infections caused by multidrug-resistant Gram-positive bacteria. The in vitro synergy test, which included a MIC assay, time-kill curve, antimicrobial susceptibility testing, and live/dead bacteria staining assay, revealed that laurocapram, a widely used chemical transdermal enhancer, could potentiate the antibacterial activity of cephalosporins against MRSA. In vitro, laurocapram combined with cefixime showed an excellent synergistic activity against MRSA (FICI = 0.28 ± 0.00). In addition, the combination of laurocapram and cefixime may inhibited the formation of MRSA biofilm and caused cell membrane damage. Following that, we discovered that combining laurocapram with cefixime could alleviate the symptoms of mice in the MRSA skin infection model and the MRSA pneumonia model. In conclusion, laurocapram is a promising and low-cost antibacterial adjuvant, providing a new strategy for further exploring the use of lower doses of cephalosporins to combat MRSA infection.

Protium spruceanum Extract Enhances Mupirocin Activity When Combined with Nanoemulsion-Based Hydrogel: A Multi-Target Strategy for Treating Skin and Soft Tissue Infections.

The treatment of skin and soft tissue infections (SSTIs) can be challenging due to bacterial resistance, particularly from strains like MRSA and biofilm formation. However, combining conventional antibiotics with natural products shows promise in treating SSTIs. The objective of this study is to develop a nanoemulsion-based hydrogel containing Protium spruceanum extract and mupirocin and evaluate its potential for the treatment of SSTIs. The nanoemulsion was obtained by phase inversion and subsequently characterized. The antibacterial activity was evaluated in vitro against S. aureus MRSA, including the synergism of the combination, changes in membrane permeability using flow cytometry, and the anti-biofilm effect. In addition, the irritative potential was evaluated by the HET-CAM assay. The combination exhibited synergistic antibacterial activity against S. aureus and MRSA due to the extract enhancing membrane permeability. The hydrogel demonstrated suitable physicochemical properties, inhibited biofilm formation, and exhibited low irritation. The formulation was nanometric (176.0 ± 1.656 nm) and monodisperse (polydispersity index 0.286 ± 0.011). It exhibited a controlled release profile at 48 h and high encapsulation efficacy (94.29 ± 4.54% for quercitrin and 94.20 ± 5.44% for mupirocin). Therefore, these findings suggest that the hydrogel developed could be a safe and effective option for treating SSTIs.

Trichilia catigua against Helicobacter pylori: An in vitro, molecular and in silico approach.

Helicobacter pylori is a bacterium that is present in the stomach of about 50% of the global population and is associated with several gastric disorders, including cancer. Natural products with antimicrobial activity have been tested against H. pylori, among them Trichilia catigua (catuaba), which is widely distributed in Brazil. This study aimed to evaluate extracts of T. catigua bark against H. pylori via determination of the minimum inhibitory and bactericidal concentrations (MIC and MBC); evaluation of virulence factors by real-time PCR, synergism with standard antimicrobials and morphology by scanning electron microscopy and simulations of the mechanism of action by molecular docking. The ethyl acetate fraction provided the best results, with an MIC50 of 250 µg/mL and a 42.34% reduction in urease activity, along with reduced expression of the CagA and VacA genes, which encode for the main virulence factors. This fraction presented synergistic activity with clarithromycin, reducing the MIC of the drug by four-fold. Docking simulations suggested that the extracts inhibit fatty acid synthesis by the FAS-II system, causing damage to the cell membrane. Therefore, T. catigua extracts have potential as an adjuvant to treatment and are promising for the development of new anti-H. pylori drugs.

Potential antifungal applications of heterometallic silica nanohybrids: A synergistic activity.

An estimated 1.7 million fatalities and 150 million cases worldwide are attributed to fungal infections annually, that are in rise due to immunocompromised patient population. The challenges posed by traditional treatments can be addressed with the help of nanotechnology advancements. In this study, Co, Cu, and Ag-were doped into silica nanoparticles. Then the synthesized monometallic silica nanohybrids were combined to formulate heterometallic silica nanohybrids, characterized structurally and morphologically, compared, and evaluated for antifungal activity based on their individual and synergistic activity. The antifungal assays were conducted by using ATCC cultures of Candida albicans and QC samples of Trichophyton rubrum, Microsporum gypseum, and Aspergillus niger. The MIC (ranging from 49.00 to 1560.00 µg/mL), MFC (ranging from 197.00 to 3125.00 µg/mL), IC50 values (ranging from 31.10 to 400.80 µg/mL), and FICI of nanohybrids were determined and compared. Moreover, well diffusion assay was performed. ABTS assay and DPPH assay were conducted to investigate the radical scavenging activity (RSA) of nanohybrids. SEM analysis clearly evidenced the structural deformations of each fungal cells and spores due to the treatment with trimetallic nanohybrid. According to the results, the trimetallic silica nanohybrids exhibited the most powerful synergistic RSA and the most effective antifungal activity, compared to the bimetallic silica nanohybrids.

Assessing the synergistic potential of bacteriophage endolysins and antimicrobial peptides for eradicating bacterial biofilms.

Phage-encoded endolysins have emerged as a potential substitute to conventional antibiotics due to their exceptional benefits including host specificity, rapid host killing, least risk of resistance. In addition to their antibacterial potency and biofilm eradication properties, endolysins are reported to exhibit synergism with other antimicrobial agents. In this study, the synergistic potency of endolysins was dissected with antimicrobial peptides to enhance their therapeutic effectiveness. Recombinantly expressed and purified bacteriophage endolysin [T7 endolysin (T7L); and T4 endolysin (T4L)] proteins have been used to evaluate the broad-spectrum antibacterial efficacy using different bacterial strains. Antibacterial/biofilm eradication studies were performed in combination with different antimicrobial peptides (AMPs) such as colistin, nisin, and polymyxin B (PMB) to assess the endolysin's antimicrobial efficacy and their synergy with AMPs. In combination with T7L, polymyxin B and colistin effectively eradicated the biofilm of Pseudomonas aeruginosa and exhibited a synergistic effect. Further, a combination of T4L and nisin displayed a synergistic effect against Staphylococcus aureus biofilms. In summary, the obtained results endorse the theme of combinational therapy consisting of endolysins and AMPs as an effective remedy against the drug-resistant bacterial biofilms that are a serious concern in healthcare settings.

Antibiotic potentiating effect of Bauhinia purpurea L. against multidrug resistant Staphylococcus aureus.

Bauhinia purpurea L. is a medium-sized tree from the family Fabaceae. The plant is traditionally used as medicine by different tribes in Sikkim. The present study aimed to evaluate the modulation in minimum inhibitory concentration (MIC) of the bark methanol extract of Bauhinia purpurea L. against the clinical isolates of multidrug resistant Staphylococcus aureus. The synergistic activity of the test plant extract with different classes of antibiotics was also evaluated. The methanol extract of Bauhinia purpurea exhibited modulation by a 16-fold reduction in the MIC of clindamycin against both resistant and susceptible isolates, followed by penicillin and gentamicin, whereas a maximum of only a 4-fold MIC reduction was observed with ciprofloxacin. The lowest minimum inhibitory concentration and minimum bactericidal concentration showed by the plant extract was 0.48 and 0.97 mg/mL, respectively. The methanol extract of Bauhinia purpurea exhibited synergistic activity with penicillin, gentamicin, ciprofloxacin, and clindamycin against most of the tested isolates of multidrug-resistant Staphylococcus aureus (MDR-SA). Gas chromatography-mass spectrometry analysis of Bauhinia purpurea L. bark methanol extract revealed 16 phytocompounds. The results provide an insight into the potential antibacterial property of the plant extract in terms of its antibiotic MIC modulation and synergistic properties with the selected antibiotics. This is the first report of the antibiotic potentiation property of Bauhinia purpurea L., collected from Sikkim, India.

Study on synergistic effects of curcumin and bixin against foodborne pathogens.

Various studies have shown that natural colorants, in addition to their coloring attributes, have valuable biological effects such as antioxidant, anti-inflammation, and anticarcinogenic properties. Moreover, their use as a food colorant can restrict the potential disadvantages of synthetic additives and turn foods into functional products. In this study, in vitro antimicrobial activities of two natural colorants of bixin and curcumin against some important foodborne pathogens: Staphylococcus aureus (S. aureus), Listeria innocua (L. innocua), and Escherichia coli (E. coli) were investigated by disk diffusion method. Minimum inhibitory concentration and minimum bactericidal concentration values were determined by agar dilution and broth microdilution methods. The synergistic activity of the colorants against selected microorganisms was assayed by the checkerboard microdilution method. The results showed that the inhibitory effects of bixin against S. aureus were more pronounced than E. coli and L. innocua. The lowest concentration of curcumin (0.6 mg/mL) in the disk diffusion method was not inhibited by any tested bacteria. However, it was effective at the higher concentrations against three microorganisms, but its diameter of inhibition zones was lower than gentamicin in all concentrations. Synergetic effects were observed by curcumin and bixin combination against S. aureus (FICI ≤ 0.5), but they act as an antagonist against E. coli and L. innocua. The results of the synergy test were confirmed by the isobologram curves.

Efficacy and Synergistic Potential of Cinnamon (Cinnamomum zeylanicum) and Clove (Syzygium aromaticum L. Merr. & Perry) Essential Oils to Control Food-Borne Pathogens in Fresh-Cut Fruits.

The presence of microbial pathogens in ready-to-eat produce represents a serious health problem. The antibacterial activity of cinnamon (Cinnamomum zeylanicum) and clove (Syzygium aromaticum L. Merr. & Perry) essential oils (EOs) was determined toward food-borne pathogens by agar disk diffusion and minimum inhibitory concentration (MIC) assays. The growth kinetics of all strains, both in a buffer suspension assay and "on food" in artificially contaminated samples, were also investigated. The two EOs demonstrated a good antibacterial effect both alone and in combination (EO/EO). The use of EO/EO led to a synergistic antibacterial effect, also confirmed by the growth kinetics studies, where the EOs were active after 10 h of incubation (p < 0.0001) at significantly lower concentrations than those when alone. In the "on food" studies performed on artificially contaminated fruit samples stored at 4 °C for 8 days, the greatest killing activity was observed at the end of the trial (8 days) with a reduction of up to 7 log CFU/g compared to the control. These results confirm the good antibacterial activity of the EOs, which were more effective when used in combination. Data from the "on food" studies suggest cinnamon and clove essential oils, traditionally used in the food industry, as a possible natural alternative to chemical additives.

Susceptibility and Synergistic Effects of Guava Plant Extract and Antimicrobial Drugs on Escherichia coli.

Introduction Psidium guajava (guava) is a fruit plant of the Myrtaceae family. Guava roots, leaves, and fruits have traditionally been used to prevent and treat various infections. In the last few decades, there has been exponential growth in herbal medicine. Therefore, the present study was conducted to determine the susceptibility and synergistic properties of the antimicrobial activity of the aqueous leaf extract of guava and other antimicrobial drugs against Escherichia coli (E. coli). Methodology A prospective observational study was conducted at the Department of Microbiology, MGM Medical College and Hospital, Navi Mumbai, India, involving 180 urine samples collected from patients who exhibited symptoms of urinary tract infection (UTI). The aim was to evaluate in vitro synergism between leaf extracts of guava and antimicrobial drugs on uropathogenic E. coli, using minimal inhibitory concentration (MIC) and the Kirby-Bauer method. The Kirby-Bauer disc diffusion method was employed to determine the synergistic activity using Muller-Hinton agar (MHA), and the zone of inhibition was measured in millimeters. Results The study found that, of the 180 urine samples collected from patients with UTI, significant growth was observed in 93 samples, with the most notable increase seen in E. coli. The antibiotics tobramycin, ofloxacin, and amikacin, each showing a sensitivity of 76% and 70% respectively, were found to be the most sensitive. Conversely, cefuroxime and cephalothin, both at 76%, were the most resistant. Furthermore, the antibiotic sensitivity pattern of E. coli without guava extract demonstrated tobramycin (TOB) at 76.66%, followed by ofloxacin (OF) and amikacin (AK) at 70% each, levofloxacin (LE) at 63.33%, nitrofurantoin (NIT) at 53.33%, trimethoprim (TR) at 43.33%, cefotaxime (CTX) at 36.66%, ceftizoxime (CZX) at 30%, norfloxacin (NR) at 26.66%, cephalothin (CEP) at 23.33%, amoxicillin-clavulanate (AMC) at 20%, and cefuroxime (CXM) at 10%. In contrast, when the antibiotic sensitivity pattern of E. coli with guava extract was examined, the highest sensitivity was noted for OF (100%), followed by LE (96.66%), TOB (93.33%), AK (90%), NIT (76.66%), AMC and TR (66.66% each), CTX (60%), CZX (53.33%), CEP (50%), NX (43.33%), and CXM (26.66%). Therefore, Psidium guajava (guava) extract exhibited a synergistic effect when combined with antibiotics, most notably with ofloxacin. Conclusion The study revealed that the highest synergistic activity of guava plant leaf extract was with the antibiotic ofloxacin. This finding indicates that guava extract enhances the effectiveness of commonly used antibiotics for treating UTI, an effect mainly attributed to the flavonoid compounds and their derivatives in the guava leaf extract, which inhibit bacterial growth. This study demonstrated the antibacterial properties of guava, suggesting that combining antibiotics with guava extract can help delay the emergence of bacterial resistance.

Synergistic antibacterial activity of Phyllanthus emblica fruits and its phytocompounds with ampicillin: a computational and experimental study.

Phyllanthus emblica L. (syn. Emblica officinalis), popularly known as amla, Indian gooseberry, or the King of Rasyana, is a member of Phyllanthaceae family and is traditionally used in Ayurveda as an immunity booster. The present study aimed to investigate the synergistic interaction of Phyllanthus emblica (FPE) fruits and its selected phytocompounds with ampicillin against selected bacteria. Further, an in silico technique was used to find if major phytocompounds of FPE could bind to proteins responsible for antibiotic resistance in bacterial pathogens and enhance the bioactivity of ampicillin. FPE and all the selected phytocompounds were found to have synergistic antibacterial activity with ampicillin against tested bacteria in different combinations. However, ellagic acid and quercetin interactions with ampicillin resulted in maximum bioactivity enhancement of 32-128 folds and 16-277 folds, respectively. In silico analysis revealed strong ellagic acid, quercetin, and rutin binding with penicillin-binding protein (PBP-) 3, further supported by MD simulations. Ellagic acid and quercetin also fulfill Lipinski's rule, showing similar toxicity characteristics to ampicillin. FPE showed synergistic interaction with ampicillin, possibly due to the presence of phytocompounds such as gallic acid, ellagic acid, quercetin, and rutin. Molecular docking and MD simulations showed the strong interaction of ellagic acid and quercetin with PBP-3 protein. Therefore, these compounds can be explored as potential non-toxic drug candidates to combat bacterial antimicrobial resistance.

Can nonsteroidal anti-inflammatory drugs (NSAIDs) be repurposed for fungal infection?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of anti-inflammatory drugs widely used for the treatment of musculoskeletal disorders, mild-to-moderate pain, and fever. This review aimed to explain the functional role and possible mechanisms of the antifungal effects of NSAIDs alone or in combination with antifungal drugs in vitro and in vivo. Several studies reported that NSAIDs such as aspirin, ibuprofen, diclofenac, indomethacin, ketorolac, celecoxib, flurbiprofen, and nimesulide had antifungal activities in vitro, either fungistatic or fungicidal, against different strains of Candida, Aspergillus, Cryptococcus, Microsporum, and Trichophyton species. These drugs inhibited biofilm adhesion and development, and yeast-to-hypha conversion which may be related to a prostaglandin E2 (PGE2)/PGEx-dependent mechanism. Modulating PGE2 levels by NSAIDs during fungal infection can be introduced as a possible mechanism to overcome. In addition, some important mechanisms of the antifungal activities of NSAIDs and their new derivatives on fungi and host immune responses are summarized. Overall, we believe that using NSAIDs along with classical antifungal drugs has the potential to be investigated as a novel therapeutic strategy in clinical studies. Furthermore, combination therapy can help manage resistant strains, increase the efficacy of antifungal drugs, and reduce toxicity.

Functional study of a lytic polysaccharide monooxygenase MsLPMO3 from Morchella sextelata in the oxidative degradation of cellulose.

Lytic polysaccharide monooxygenases (LPMOs) can improve the effectiveness with which agricultural waste is utilized. This study described the potent AA9 family protein MsLPMO3, derived from Morchella sextelata. It exhibited strong binding to phosphoric acid swollen cellulose (PASC), and had the considerable binding ability to Cu2+ with a Kd value of 2.70 µM by isothermal titration calorimetry (ITC). MsLPMO3 could also act on PASC at the C1 carbon via MALDI-TOF-MS results. Moreover, MsLPMO3 could boost the hydrolysis efficiency of corncob and wheat bran in combination with glycoside hydrolases. MsLPMO3 also exhibited strong oxidizing ability for 2,6-dimethoxyphenol (2,6-DMP), achieving the best Vmax value of 443.36 U·g-1 for pH 7.4 with a H2O2 concentration of 300 µM. The structure of MsLPMO3 was obtained using AlphaFold2, and the molecular docking results elucidated the specific interactions and key residues involved in the recognition process between MsLPMO3 and cellulose. Altogether, this study expands the knowledge of AA9 family proteins in cellulose degradation, providing valuable insights into the mechanisms of synergistic degradation of lignocellulose with cellulases.

Microalga Broths Synthesize Antibacterial and Non-Cytotoxic Silver Nanoparticles Showing Synergy with Antibiotics and Bacterial ROS Induction and Can Be Reused for Successive AgNP Batches.

The era of increasing bacterial antibiotic resistance requires new approaches to fight infections. With this purpose, silver-based nanomaterials are a reality in some fields and promise new developments. We report the green synthesis of silver nanoparticles (AgNPs) using culture broths from a microalga. Broths from two media, with different compositions and pHs and sampled at two growth phases, produced eight AgNP types. Nanoparticles harvested after several synthesis periods showed differences in antibacterial activity and stability. Moreover, an evaluation of the broths for several consecutive syntheses did not find relevant kinetics or activity differences until the third round. Physicochemical characteristics of the AgNPs (core and hydrodynamic sizes, Z-potential, crystallinity, and corona composition) were determined, observing differences depending on the broths used. AgNPs showed good antibacterial activity at concentrations producing no or low cytotoxicity on cultured eukaryotic cells. All the AgNPs had high levels of synergy against Escherichia coli and Staphylococcus aureus with the classic antibiotics streptomycin and kanamycin, but with ampicillin only against S. aureus and tetracycline against E. coli. Differences in the synergy levels were also dependent on the types of AgNPs. We also found that, for some AgNPs, the killing of bacteria started before the massive accumulation of ROS.

PYED-1 Overcomes Colistin Resistance in Acinetobacter baumannii.

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin.

Combining the Peptide RWQWRWQWR and an Ethanolic Extract of Bidens pilosa Enhances the Activity against Sensitive and Resistant Candida albicans and C. auris Strains.

The antifungal activity of palindromic peptide RWQWRWQWR and its derivatives was evaluated against clinical isolates of Candida albicans and C. auris. Also, Bidens pilosa ethanolic extracts of leaves and stem were evaluated. Furthermore, combinations of peptide, extract, and/or fluconazole (FLC) were evaluated. The cytotoxicity of peptides and extracts in erythrocytes and fibroblasts was determined. The original palindromic peptide, some derivative peptides, and the ethanolic extract of leaves of B. pilosa exhibited the highest activity in some of the strains evaluated. Synergy was obtained between the peptide and the FLC against C. auris 435. The combination of the extract and the original palindromic peptide against C. albicans SC5314, C. auris 435, and C. auris 537 decreased the minimal inhibitory concentrations (MICs) by a factor of between 4 and 16. These mixtures induced changes in cell morphology, such as deformations on the cell surface. The results suggest that the combination of RWQWRWQWR and B. pilosa extract is an alternative for enhancing antifungal activity and decreasing cytotoxicity and costs and should be considered to be a promising strategy for treating diseases caused by Candida spp.

Evaluation of deoxythymidine-based cationic amphiphiles as antimicrobial, antibiofilm, and anti-inflammatory agents.

OBJECTIVES: We recently designed a series of cationic deoxythymidine-based amphiphiles that mimic the cationic amphipathic structure of antimicrobial peptides (AMPs). Among these amphiphiles, ADG-2e and ADL-3e displayed the highest selectivity against bacterial cells. In this study, ADG-2e and ADL-3e were evaluated for their potential as novel classes of antimicrobial, antibiofilm, and anti-inflammatory agents. METHODS: Minimum inhibitory concentrations of ADG-2e and ADL-3e against bacteria were determined using the broth microdilution method. Proteolytic resistance against pepsin, trypsin, α-chymotrypsin, and proteinase K was determined by radial diffusion and HPLC analysis. Biofilm activity was investigated using the broth microdilution and confocal microscopy. The antimicrobial mechanism was investigated by membrane depolarization, cell membrane integrity analysis, scanning electron microscopy (SEM), genomic DNA influence and genomic DNA binding assay. Synergistic activity was evaluated using checkerboard method. Anti-inflammatory activity was investigated using ELISA and RT-PCR. RESULTS: ADG-2e and ADL-3e showed good resistance to physiological salts and human serum, and a low incidence of drug resistance. Moreover, they exhibit proteolytic resistance against pepsin, trypsin, α-chymotrypsin, and proteinase K. ADG-2e and ADL-3e were found to kill bacteria by an intracellular target mechanism and bacterial cell membrane-disrupting mechanism, respectively. Furthermore, ADG-2e and ADL-3e showed effective synergistic effects when combined with several conventional antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Importantly, ADG-2e and ADL-3e not only suppressed MDRPA biofilm formation but also effectively eradicated mature MDRPA biofilms. Furthermore, ADG-2e and ADL-3e drastically decreased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gene expression and protein secretion in lipopolysaccharide (LPS)-stimulated macrophages, implying potent anti-inflammatory activity in LPS-induced inflammation. CONCLUSION: Our findings suggest that ADG-2e and ADL-3e could be further developed as novel antimicrobial, antibiofilm, and anti-inflammatory agents to combat bacterial infections.

Naringenin-Capped Silver Nanoparticles Amalgamated Gel for the Treatment of Cutaneous Candidiasis.

The current research was aimed to synthesize a phytomolecule, naringenin (NRG)-mediated silver nanoparticles (NRG-SNPs) to study their antifungal potential against Candida albicans (C. albicans) and Candida glabrata (C. glabrata). The NRG-SNPs were synthesized by using NRG as a reducing agent. The synthesis of NRG-SNPs was confirmed by a color change and surface plasmon resonance (SPR) peak at 425 nm. Furthermore, the NRG-SNPs were analyzed for size, PDI, and zeta potential, which were found to be 35 ± 0.21 nm, 0.19 ± 0.03, and 17.73 ± 0.92 mV, respectively. In silico results demonstrated that NRG had a strong affinity towards the sterol 14α-demethylase. The docking with ceramide revealed the skin permeation efficiency of the NRG-SNPs. Next, the NRG-SNPs were loaded into the topical dermal dosage form (NRG-SNPs-TDDF) by formulating a gel using Carbopol Ultrez 10 NF. The MIC50 of NRG solution and TSC-SNPs against C. albicans was found to be 50 µg/mL and 4.8 µg/mL, respectively, significantly (P < 0.05) higher than 0.3625 µg/mL of NRG-SNPs-TDDF. Correspondingly, MIC50 results were calculated against C. glabrata and the results of NRG, TSC-SNPs, NRG-SNPs-TDDF, and miconazole nitrate were found to be 50 µg/mL, 9.6 µg/mL, 0.3625 µg/mL, and 3-µg/mL, respectively. Interestingly, MIC50 of NRG-SNPs-TDDF was significantly (P < 0.05) lower than MIC50 of miconazole nitrate against C. glabrata. The FICI (fractional inhibitory concentration index) value against both the C. albicans and C. glabrata was found to be 0.016 and 0.011, respectively, which indicated the synergistic antifungal activity of NRG-SNPs-TDDF. Thus, NRG-SNPs-TDDF warrants further in depth in vivo study under a set of stringent parameters for translating in to a clinically viable antifungal product.