Novel synergistic interactions between monolaurin, a mono-acyl glycerol and ß lactam antibiotics against Staphylococcus aureus: an in vitro study.

BACKGROUND: A major worldwide health issue is the rising frequency of resistance of bacteria.Drug combinations are a winning strategy in fighting resistant bacteria and might help in protecting the existing drugs.Monolaurin is natural compound extracted from coconut oil and has a promising antimicrobial activity against Staphylococcus.aureus. This study aims to examine the efficacy of monolaurin both individually and in combination with ß-lactam antibiotics against Staphylococcus aureus isolates. METHODS: Agar dilution method was used for determination of minimum inhibitory concentration (MIC) of monolaurin against S.aureus isolates. Scanning electron microscope (SEM) was used to detect morphological changes in S.aureus after treatment with monolaurin. Conventional and Real-time Polymerase chain reaction (RT-PCR) were performed to detect of beta-lactamase (blaZ) gene and its expressional levels after monolaurin treatment. Combination therapy of monolaurin and antibiotics was assessed through fractional inhibitory concentration and time-kill method. RESULTS: The antibacterial activity of monolaurin was assessed on 115 S.aureus isolates, the MIC of monolaurin were 250 to 2000 µg/ml. SEM showed cell elongation and swelling in the outer membrane of S.aureus in the prescence of 1xMIC of monolaurin. blaZ gene was found in 73.9% of S.aureus isolates. RT-PCR shows a significant decrease in of blaZ gene expression at 250 and 500 µg/ml of monolaurin. Synergistic effects were detected through FIC method and time killing curve. Combination therapy established a significant reduction on the MIC value. The collective findings from the antibiotic combinations with monolaurin indicated synergism rates ranging from 83.3% to 100%.In time-kill studies, combination of monolaurin and ß-lactam antibiotics produced a synergistic effect. CONCLUSION: This study showed that monolaurin may be a natural antibacterial agent against S. aureus, and may be an outstanding modulator of ß-lactam drugs. The concurrent application of monolaurin and ß-lactam antibiotics, exhibiting synergistic effects against S. aureus in vitro, holds promise as potential candidates for the development of combination therapies that target particularly, patients with bacterial infections that are nearly incurable.

Nano-ciprofloxacin/meropenem exhibit bactericidal activity against Gram-negative bacteria and rescue septic rat model.

Aim: We hypothesized that simultaneous administration of two antibiotics loaded into a nanopolymer matrix would augment their synergistic bactericidal interaction. Methods: Nanoplatforms of chitosan/Pluronic® loaded with ciprofloxacin/meropenem (CS/Plu-Cip/Mer) were prepared by the ionic gelation method, using Plu at concentrations in the range 0.5-4% w/v. CS/Plu-Cip/Mer was evaluated for antibacterial synergistic activity in vitro and in vivo. Results: CS/Plu-Cip and CS/Plu-Mer with Plu concentrations of 3% w/v and 2% w/v, respectively, exhibited ∼80% encapsulation efficiency. The MICs of pathogens were fourfold to 16-fold lower for CS/Plu-Cip/Mer than for Cip/Mer. Synergy was evidenced for CS/Plu-Cip/Mer with a bactericidal effect (at 1× MIC and sub-MICs), and it significantly decreased bacterial load and rescued infected rats. Conclusion: This study illustrates the ability of CS/Plu nanopolymer to intensify synergy between antibiotics, thereby providing a promising potential to rejuvenate antibiotics considered ineffective against resistant pathogens.

Antibiotics are used to treat bacterial infections. However, the more they are used, the less effective they become, because bacteria develop resistance to them. One strategy to overcome this is to treat bacterial infection with a combination of antibiotics that work well together. The antibiotics ciprofloxacin and meropenem are often given together to treat Pseudomonas aeruginosa, a bacterium which can cause sepsis, a type of blood poisoning. Another strategy to overcome antibiotic resistance is to load them into nanocarriers, which can change their properties. Nanocarrier-loaded antibiotics can reduce toxicity and increase effectiveness. This study investigated whether the effectiveness of this pair could be improved by loading them into nanoparticles. When these nanoparticles were given to rats with sepsis, they were significantly more effective than unloaded ciprofloxacin and meropenem combinations. These nanoparticles were also able to directly kill bacteria, rather than just prevent bacterial reproduction, as with the unloaded combination. This study demonstrates that nanocarrier loading can intensify the enhanced benefit of combined antibiotic treatments. This is a promising strategy to reuse antibiotics that have become ineffective at treating bacteria which have developed resistance.

Nanosized Combined Antimicrobial Drugs Decreased Emergence of Resistance in Escherichia coli: A Future Promise.

Antibiotic combinations remain the frontline therapy for severe infections to reduce mortality. However, conventional antibiotic combinations have some limitations such as the low bioavailability and the rise of resistant strains. Nanoparticles are increasingly used as antibiotic delivery systems to promote bioavailability and hence improve efficacy of antibiotics. In this work, we hypothesize that the simultaneous delivery of two antibiotic-loaded nanoparticles will improve the intracellular bioavailability and thus inhibit emergence of resistance. Accordingly, Chitosan-pluronic nanoparticles were used to construct nanosized ciprofloxacin and meropenem and the antibacterial activity of nanosized combined antibiotics were compared versus unloaded single, unloaded combined, and nanosized single antibiotics. Thirty-six stepwise mutants were selected by exposing two E. coli strains to increasing concentrations of free-unloaded and nanosized antibiotics, and mutants were tested for antimicrobial susceptibilities using broth microdilution and disc diffusion methods. The change in expression levels of acrB efflux pump and porins (ompC and ompF) was assessed by real-time reverse transcription-PCR. The in vitro evaluation of combined ciprofloxacin and meropenem-loaded nanoparticles demonstrated that this nanosystem exhibited enhanced antibacterial effect. Step mutants selected with nanosized combined antibiotics showed higher sensitivity to both drugs, exhibited lower mutation frequencies, and less cross-resistance to other antimicrobial classes. Moreover, for all steps of selection, nanosized combined antibiotic mutants expressed significantly lower levels of acrB as well as higher levels of ompC and ompF (p-value <0.01). In view of these results, the use of nanosized combined antibiotics may be considered among the new promising strategies to combat infections through their potential efficacy in reducing microorganisms' ability to form resistant mutants.

Diagnostic value of monocyte chemoattractant Protein-1, soluble mannose receptor, Presepsin, and Procalcitonin in critically ill children admitted with suspected sepsis.

INTRODUCTION: The differentiation between systemic inflammatory response syndrome and sepsis is very important as it determines essential treatment decisions, such as selection, initiation, and duration of antibiotic therapy. OBJECTIVES: We aimed to investigate the diagnostic value of Procalcitonin, Monocyte Chemoattractant Protein-1, soluble Mannose Receptor, Presepsin as early biomarkers of pediatric sepsis in comparison to systemic inflammatory response syndrome in severely ill children. PATIENTS AND METHODS: This study included 58 children diagnosed as sepsis (group 1), 24 children with systemic inflammatory response syndrome without infection (group 2), and 50 healthy children as controls (group 3). All the plasma levels of the studied biomarkers were measured and ROC curves were created for all the tested parameters to discriminate between sepsis and SIRS. RESULTS: The area under the curve for Monocyte Chemoattractant Protein-1 was 0.926 (0.846-0.927) with sensitivity 100% and specificity 62.5%. The soluble Mannose Receptor had the highest sensitivity (100%), with AUC equals 1(.0.956-1.0) and specificity of 100%. The cut-off values for Procalcitonin, Presepsin, soluble Mannose Receptor, and Monocyte Chemoattractant Protein-1 and were: 0.62 ng/ml, 100 pg/ml, 13 ng/ml and 90 pg/ml, respectively. In septic cases, both soluble Mannose Receptor and Procalcitonin have positive correlations with the severity of sepsis, low Glasgow Coma Scale, ventilatory support, use of inotropic drugs and mortality rate (r = 0.950, 0.812, 0.795, 0.732 and 0.861respectively) for soluble Mannose Receptor and (0.536, 0.473, 0.422, 0.305 and 0.474 respectively) for Procalcitonin. CONCLUSION: Soluble Mannose Receptor, Presepsin, and Monocyte Chemoattractant Protein-1 can be used to differentiate between sepsis and SIRS in critically ill children.

Design, synthesis, mechanistic studies and in silico ADME predictions of benzimidazole derivatives as novel antifungal agents.

Herein, novel three series of benzimidazole scaffold bearing hydrazone, 1,2,4-triazole and 1,3,4-oxadiazole moieties 1-3, 4a-j, 6a-c and 7 derivatives were designed, synthesized and evaluated for their antimicrobial activity. The structures of the prepared compounds were assigned using different spectroscopic techniques such as IR, 1H NMR, 13C NMR and elemental analyses. Compounds 3, 4a, 4e and 4f exhibited remarkable antifungal activity against C. albicans and C. neoformans var. grubii with MIC values ranging from 4 to 16 µg/mL. Furthermore, they were not cytotoxic against red blood cells and human embryonic kidney cells at concentration up to 32 µg/mL. The study was expanded to forecast the mechanism of action of the prepared compounds and determine sterol quantitation method (SQM) by spectrophotometric assay. On the other hand, compound 4e showed the highest inhibitory activity against lanosterol 14α-demethylase (CYP51) with IC50 value = 0.19 µg/mL compared to fluconazole as reference IC50 value = 0.62 µg/mL. Also, compounds 4d and 4f exhibited mild to moderate antibacterial activity. Moreover, molecular docking of the active target compound 4e in active site of lanosterol 14α-demethylase (CYP51) revealed that docking scores and binding mode are comparable to that of co-crystallized ligand confirming their antifungal activity. In silico ADME prediction investigations also forecasting the drug-like characters of these compounds.