Lipopolysaccharide induced neuroprotective effects of bacterial protease against Alzheimer's disease in male Wistar albino rats.

Alzheimer's disease (AD) is a highly severe neurodegenerative condition that affects the hippocampus and is characterized by memory loss and dementia. This investigation aims to determine the potential of a bacterial protease enzyme produced by a new mutant strain of bacteria (Bacillus cereus S6-3/UM90) to influence the rat behavioural, biochemical, histological, and immuno-histochemical functions induced by lipopolysaccharides (LPS) experimentally. The administration of LPS exhibited a decline in memory performance via Morris' Water Maze test along with an elevation of IL-6, IL-17, amino acid neurotransmitters, Adenosine monophosphate (AMP), and 8-OHdG, whereas a decrease in ATP (Adenosine Triphosphate), monoamine transmitters, AChE (acetylcholinesterase) and PC (phosphatidylcholine). Additionally, there was a notable increase in GFAP (glial fibrillary acidic protein) and p-Tau protein immuno-expression levels along with obvious histological lesions in the hippocampal CA3 region. Moreover, the administration of protease or Donepezil restored the measured parameters to nearly normal levels and improved the histological architecture of the hippocampus and ameliorated memory impairments. In conclusion, the study provides evidence that the treatment with Bacterial protease can improve the memory and learning impairments of LPS-induced AD and may be used as a promising therapeutic agent to manage AD since it has anti-inflammatory and antioxidant effects.

Synergistic activity and molecular modelling of fosfomycin combinations with some antibiotics against multidrug resistant Helicobacter pylori.

Antibiotic resistance represents the main challenge of Helicobacter pylori infection worldwide. This study investigates the potential bactericidal effects of fosfomycin combinations with clarithromycin, metronidazole, ciprofloxacin, amoxicillin, rifampicin, and doxycycline against thirty-six H. pylori strains using the checkerboard and time-kill assay methods. The results showed that ≥ 50% of the strains were resistant to the six antibiotics. Remarkably, only six strains exerted resistance to these antibiotics, with the minimum inhibitory concentrations (MICs) ranges of (3.2-12.8 mg/l), (32-256 mg/l), (3.2-51.2 mg/l), (3.2-25.6 mg/l), (1.6-3.2 mg/l), and (25.6 > 51.2 mg/l), respectively. The seven antibiotics were evaluated through in silico studies for their permeability and ability to bind UDP-N-acetylglucosamine1-carboxyvinyltransferase (MurA) of H. pylori. The results indicated that fosfomycin exhibited the highest predicted membrane permeability (membrane ∆G insert = - 37.54 kcal/mol) and binding affinity (docking score = - 5.310 kcal/mol) for H. pylori MurA, compared to other tested antibiotics. The combinations of fosfomycin with these antibiotics exerted synergistic interactions (Fractional inhibitory concentration, FIC index < 1) against the six strains. Importantly, the combinations of fosfomycin with clarithromycin, doxycycline and rifampicin achieved bactericidal effects (reduction ≥ 3.0 Log10 cfu/ml) against the most resistant H. pylori strain. Notably, these effects increased with presence of metronidazole, which enhanced the activity of the fosfomycin combination with amoxicillin from a weak inhibition to bactericidal effect. This study provides evidence that the combination of fosfomycin with either clarithromycin, amoxicillin, doxycycline, or rifampicin (especially with the presence of metronidazole) could be a promising option for treating MDR H. pylori infection.

In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans.

The resistance of Candida albicans to azole drugs represents a great global challenge. This study investigates the potential fungicidal effects of atorvastatin (ATO) combinations with fluconazole (FLU), itraconazole (ITR), ketoconazole (KET) and voriconazole (VOR) against thirty-four multidrug-resistant (MDR) C. albicans using checkerboard and time-kill methods. Results showed that 94.12% of these isolates were MDR to ≥ two azole drugs, whereas 5.88% of them were susceptible to azole drugs. The tested isolates exhibited high resistance rates to FLU (58.82%), ITR (52.94%), VOR (47.06%) and KET (35.29%), whereas only three representative (8.82%) isolates were resistant to all tested azoles. Remarkably, the inhibition zones of these isolates were increased at least twofold with the presence of ATO, which interacted in a synergistic (FIC index ≤ 0.5) manner with tested azoles. In silico docking study of ATO and the four azole drugs were performed against the Lanosterol 14-alpha demethylase enzyme (ERG11) of C. albicans. Results showed that the mechanism of action of ATO against C. albicans is similar to that of azole compounds, with a docking score (-4.901) lower than azole drugs (≥5.0) due to the formation a single H-bond with Asp 225 and a pi-pi interaction with Thr 229. Importantly, ATO combinations with ITR, VOR and KET achieved fungicidal effects (≥ 3 Log10 cfu/ml reduction) against the representative isolates, whereas a fungistatic effect (≤ 3 Log10 cfu/ml reduction) was observed with FLU combination. Thus, the combination of ATO with azole drugs could be promising options for treating C. albicans infection.

Synergistic effects of pomegranate and rosemary extracts in combination with antibiotics against antibiotic resistance and biofilm formation of Pseudomonas aeruginosa.

The combination of plant extract and antibiotic represents a template for developing of antibiofilm drugs. This study investigated the synergistic effects of pomegranate/rosemary/antibiotic combinations against antibiotic resistance and biofilm formation of Pseudomonas aeruginosa. The results showed that 17 (85%) of total P. aeruginosa isolates were biofilm producers; however, 5 (25%) isolates were demonstrated as a strong biofilm producer. The highest MIC level (1024 µg/ml) of tested antibiotics against strong biofilm producer isolates was observed with piperacillin, however the MIC ranges of ceftazidime, gentamycin, imipenem, and levofloxacin against these isolates were reached to (256-1024 µg/ml), (32-1024 µg/ml), (8-1024 µg/ml), and (8-512 µg/ml), respectively. PS-1 was the representative isolate for strong biofilm formation and high antibiotic resistance. 16S rRNA gene analysis suggested that PS-1 (accession No. MN619678) was identified as a strain of P. aeruginosa POA1. Pomegranate and rosemary extracts were the most effective extracts in biofilm inhibition, which significantly inhibited 91.93 and 90.83% of PS-1 biofilm, respectively. Notably, the synergism between both plant extracts and antibiotics has significantly reduced the MICs of used antibiotics at the level lower than the susceptibility breakpoints. Pomegranate/rosemary/antibiotic combinations achieved the highest biofilm eradication, which ranging from 90.0 to 99.6%, followed by the eradication ranges of pomegranate/rosemary combination, rosemary, and pomegranate extracts, which reached to (76.5-85.4%), (53.1-73.7%), and (41.2-71.5%), respectively. The findings suggest that pomegranate/rosemary/antibiotic combinations may be an effective therapeutic agent for antibiotic resistance and biofilm formation of P. aeruginosa.

Evaluation of fosfomycin combined with vancomycin against vancomycin-resistant coagulase negative staphylococci.

The pathogenic potential of coagulase-negative staphylococci (CoNS) is increasingly recognized worldwide. The aim of the present study was to evaluate different combinations of fosfomycin (FOS) with vancomycin (VAN) or oxacillin (OXA) against vancomycin-resistant clinical isolates of CoNS. Characterization of VAN resistance in selected isolates was also sought. Antibiotic susceptibility of isolates was tested by disc diffusion method, MICs of antibiotics were determined by the agar dilution method, and fosfomycin combinations were evaluated by a time-kill assay according to the guidelines of the CLSI. Moreover, oxacillin and glycopeptides (vancomycin and teichoplanin) resistances were also characterized phenotypically and genotypically in this study. Out of 258 staphylococci, 52 were CoNS (20.2%). All isolates were multidrug resistant with 75% (n = 39) oxacillin-resistant, most of them with oxacillin MIC levels of >32 mg/L. Moreover, vancomycin non-susceptibility was observed in 46.2% (n = 24) of the tested isolates with MIC range of 4-32 mg/L. Identification of selected isolates revealed that S. epidermidis was the most abundant among tested CoNS, followed by S. hominis, S. saprophyticus, and interestingly S. caseolyticus. Furthermore, Synergistic and bactericidal effects of FOS + VAN combination were observed in 3 of 9 isolates after 6 h of treatment and in all studied isolates at 24 h. On the other hand, FOS + OXA combinations were ineffective. This study provides evidence that fosfomycin combination with vancomycin could be considered as a therapeutic alternative for CoNS infections. It also sheds some light on the possible emergence of the otherwise harmless bacterium S. caseolyticus as a human pathogen.