Levonadifloxacin, a recently approved benzoquinolizine fluoroquinolone, exhibits potent in vitro activity against contemporary Staphylococcus aureus isolates and Bengal Bay clone isolates collected from a large Indian tertiary care hospital.

OBJECTIVES: Levonadifloxacin (WCK 771; IV) and its prodrug alalevonadifloxacin (WCK 2349; oral) are benzoquinolizine fluoroquinolones, recently approved in India for the treatment of acute bacterial skin and skin structure infections with concurrent bacteraemia and diabetic foot infections. Ahead of its market launch, the present study aimed to assess the in vitro activity of levonadifloxacin against contemporary Staphylococcus aureus isolates collected from a large tertiary care hospital in India. Additionally, levonadifloxacin activity was tested against hVISA and Bengal Bay clone MRSA isolates. METHODS: Non-duplicate S. aureus (n = 793) isolates collected at Christian Medical College hospital, Vellore, India during 2013-19 were included in the study. MRSA isolates were identified using a cefoxitin disc diffusion assay. MICs of levonadifloxacin and comparator antibiotics were determined using the broth microdilution method. Mutations in QRDRs were identified for selected levofloxacin-non-susceptible isolates. MLST profiling was undertaken to detect the Bengal Bay clone. RESULTS: Among the 793 isolates, 441 (55.6%) were MRSA and 626 (78.9%) were non-susceptible to levofloxacin. Levonadifloxacin showed MIC50 and MIC90 values of 0.25 and 0.5 mg/L, respectively, for all S. aureus, which included hVISA and Bengal Bay clone MRSA. The potency of levonadifloxacin was 16 times superior compared with levofloxacin. CONCLUSIONS: The present study demonstrated potent activity of levonadifloxacin against contemporary S. aureus isolates, which included MRSA isolates, hVISA isolates, Bengal Bay clone isolates and a high proportion of quinolone-non-susceptible isolates. The potent activity of levonadifloxacin observed in this study supports its clinical use for the treatment of S. aureus infections.

Elucidating anti-sclerostin mechanism of baicalein using LRP6-Sclersotin complex of canonical Wnt/ß-catenin signaling pathway.

Flavonoids are polyphenolic compounds produced by plants as secondary metabolites that are known to exhibit wide range of pharmaceutical properties. Flavonoids from different medicinal plants have been used in traditional medicine to treat several musculoskeletal disorders for centuries. Of the numerous flavonoids, baicalein from Oroxylum indicum has a well-documented protective effect in skeletal health. However, studies into its influence on the canonical Wnt/ß-catenin signaling pathway for musculoskeletal disorders remain limited. With the results of our previous study, the current research investigated the molecular mechanism of baicalein to inhibit the interaction between LRP6 and sclerostin to activate the canonical Wnt/ß-catenin signaling pathway. Molecular docking revealed that baicalein docks between LRP6 and sclerostin with a binding energy of -8.4 kcal/mol and interacts with key binding residues of both the proteins. The molecular dynamics simulations predicted the stability of baicalein through 100 ns with more conformational changes observed in sclerostin than LRP6 especially in and around the PNAIG motif of loop-2 region, hinting at a possible inhibitory effect of baicalein over sclerostin. The findings of this research could pave the way for novel drug design approaches while promoting the use of natural flavonoids as potential therapeutics for musculoskeletal disorders.Communicated by Ramaswamy H. Sarma.

Synergistic combination of baicalein and rifampicin against Staphylococcus aureus biofilms.

Staphylococcus aureus, a Gram-positive bacterium, is a predominant pathogen associated with various infections. The rapid emergence of antibiotic resistance has intensified the challenge of managing fracture-related infections in severe osteoporotic patients. Rifampicin, a potent antimicrobial agent employed against fracture and implant-related infections, necessitates combination therapies due to its susceptibility to antibiotic resistance. In this study, we explored the potential of baicalein, a bioactive flavonoid from Oroxylum indicum and Scutellaria baicalensis, in combination with rifampicin against S. aureus biofilms invitro. The minimum inhibitory concentration of baicalein and rifampicin were determined as 500 µg/mL and 12.5 ng/mL respectively. The synergistic activity of baicalein and rifampicin was determined by the fractional inhibitory concentration index (FICI) using checkerboard assay. The results showed the FICI of baicalein and rifampicin was lesser than 0.5, demonstrating synergistic effect. Furthermore, the efficacy of baicalein and rifampicin, both individually and in combination, was evaluated for biofilm inhibition and eradication. Scanning electron microscopy and confocal laser microscopy also confirmed that the synergistic combinations effectively removed most of the biofilms and partially killed pre-formed biofilms. In conclusion, the findings demonstrate that baicalein is as effective as rifampicin in inhibiting and eradicating S. aureus biofilms. Their combination exhibits synergistic effect, enhancing their bactericidal effect in completely eradicating S. aureus biofilms. The findings of this research underscore the research potential of combining baicalein and rifampicin as a novel therapeutic strategy against S. aureus biofilms, offering a promising direction for future research in the treatment of fracture-related S. aureus infections.

Identification of potential sclerostin inhibiting flavonoids from Oroxylum indicum: an insilico approach.

Flavonoids are secondary metabolites that are widely found in various medicinal plants. They are known for their medicinal benefits and have been extensively used in healthcare industries and in the management of age-related diseases. This paper focuses on flavonoids from Oroxylum indicum, a significant medicinal tree in the practice of traditional Indian medicine. O. indicum has been utilized in a variety of polyherbal formulations for the management of musculoskeletal disorders, however the mechanism of action of its bioactive flavonoids remains unknown. The present study aimed to identify the flavonoids of O. indicum with the potential to target sclerostin, an antagonist of canonical Wnt signaling pathway for the treatment of bone-related disorders. Molecular docking, coarse-grained and molecular dynamics simulations were performed to screen the major flavonoids and investigate their interaction with sclerostin. Flavonoids with highest binding affinity and interacting with at least one of the amino acids of the PNAIG motif residues were selected from docking studies and subjected to further drug likeness and ADMET screening. Further screening from coarse-grained and molecular dynamic simulations results showed that baicalein, compared to other screened flavonoids, stably binds with the important residues of the LRP6 binding site of sclerostin, resulting in pronounced structural changes in the protein. These findings suggest that baicalein from O. indicum can potentially inhibit sclerostin and can elicit skeletal protective effects, providing an insight for further in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Insights into the Mechanism of Osteoporosis and the Available Treatment Options.

Osteoporosis, one of the most prevalent bone illnesses, majorly affects postmenopausal women and men over 50 years of age. Osteoporosis is associated with an increased susceptibility to fragility fractures and can result in persistent pain and significant impairment in affected individuals. The primary method for diagnosing osteoporosis involves the assessment of bone mineral density (BMD) through the utilisation of dual energy x-ray absorptiometry (DEXA). The integration of a fracture risk assessment algorithm with bone mineral density (BMD) has led to significant progress in the diagnosis of osteoporosis. Given that osteoporosis is a chronic condition and multiple factors play an important role in maintaining bone mass, comprehending its underlying mechanism is crucial for developing more effective pharmaceutical interventions for the disease. The effective management of osteoporosis involves the utilisation of appropriate pharmacological agents in conjunction with suitable dietary interventions and lifestyle modifications. This review provides a comprehensive understanding of the types of osteoporosis and elucidates the currently available pharmacological treatment options and their related mechanism of action and usage.