ABSTRACT
This study investigates quercetin complexes as potential synergistic agents against the important respiratory pathogen Streptococcus pneumoniae. Six quercetin complexes (QCX1-6) were synthesized by reacting quercetin with various metal salts and boronic acids and characterized using FTIR spectroscopy. Their antibacterial activity alone and in synergism with antibiotics was evaluated against S. pneumoniae ATCC 49619 using disc diffusion screening, broth microdilution MIC determination, and checkerboard assays. Complexes QCX-3 and QCX-4 demonstrated synergy when combined with levofloxacin via fractional inhibitory concentration indices ≤ 0.5 as confirmed by time-kill kinetics. Molecular docking elucidated interactions of these combinations with virulence enzymes sortase A and sialidase. A biofilm inhibition assay found the synergistic combinations more potently reduced biofilm formation versus monotherapy. Additionally, gene-gene interaction networks, biological activity predictions and in-silico toxicity profiling provided insights into potential mechanisms of action and safety.
Subject(s)
Anti-Bacterial Agents , Biofilms , Microbial Sensitivity Tests , Molecular Docking Simulation , Quercetin , Streptococcus pneumoniae , Streptococcus pneumoniae/drug effects , Quercetin/pharmacology , Quercetin/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Drug Synergism , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/chemistry , Bacterial Proteins/antagonists & inhibitors , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/chemistry , Aminoacyltransferases/antagonists & inhibitors , Aminoacyltransferases/metabolism , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolismABSTRACT
Isolation of novel bioactive metabolites from Streptomyces strains is a promising source for drug discovery. However, conventional screening approaches have limitations in identifying new leads due to redundant discoveries. Optimization of culture conditions is important but traditionally optimized one factor at a time, failing to consider interactions. This study addressed these gaps by enhancing metabolite production from Streptomyces thinghirensis WAE1 through statistical optimization. Various chemical and physical factors impacting metabolite production were identified. Response surface methodology with a central composite design was applied to optimize significant factors like carbon source, nitrogen source, inoculum size, pH, temperature and incubation period. This optimized production against Streptococcus pneumoniae, increasing antibacterial activity by 74.92%. Gas chromatography-mass spectrometry revealed 19 bioactive compounds, including 1,25-dihydroxyvitamin D3 inhibiting cell wall development. This highlights S. thinghirensis WAE1's potential as a bioresource and emphasizes studying metabolite production from novel Streptomyces strains to discover new antibacterial drugs.
