Pseudomonas aeruginosa is commonly found in nosocomial and life‐threatening infections in patients. Biofilms formed by P. aeruginosa exhibit much greater resistance to antibiotics than the planktonic form of the bacteria. Few groups have studied the effects of glucose, a major carbon source, and metabolite, on P. aeruginosa biofilm formation and on its metabolic pathways. In this study, we investigated the effect of glucose on the biofilm formation ability of P. aeruginosa and carried out a metabolomic analysis to identify whether glucose alters the metabolic activity of P. aeruginosa in biofilms. We found that glucose efficiently promoted P. aeruginosa biofilm formation by upregulating the expression of the extracellular polysaccharide‐related gene pslA. Treatment with glucose caused an increase in 7 metabolites (including 3‐hydroxypropionic acid, glucose‐6‐phosphate, and 2,3‐dimethylsuccinic acid) and a decrease in 18 metabolites (including myo‐inositol, glutamine, and methoxamedrine) in the biofilm. In addition, there was a synergistic effect between glucose and horse serum on biofilm formation when the two were added in combination, which also increased the resistance of biofilm to levofloxacin therapy. Thus, our work sheds light on the underlying mechanisms by which glucose may enhance biofilm formation and identifies novel targets for developing strategies to counteract biofilm formation.
Microbial biofilms are communities of surface‐adhered cells enclosed in a matrix of extracellular polymeric substances. Bacterial cells in biofilm are 10~1,000‐fold more resistant to antimicrobials than the planktonic cells. Burgeoning antibiotic resistance in Pseudomonas aeruginosa biofilm has necessitated the development of antimicrobial agents. Here, we have investigated the antibiofilm effect of meloxicam against P. aeruginosa PAO1 and its potential mechanisms. Further, we have explored whether meloxicam could enhance the susceptibility of bacterial biofilms to treatment with conventional antimicrobials. Here, we found that meloxicam could significantly inhibit PAO1 biofilm formation in a dose‐dependent manner at the concentration without influence on planktonic cell growth. Meloxicam could also significantly inhibit the motilities, production of extracellular matrix, and expression of quorum sensing‐related genes and virulence factors of PAO1. Furthermore, synergistic interaction was observed when meloxicam combined with tetracycline, gentamicin, tobramycin, ciprofloxacin, ceftriaxone, ofloxacin, norfloxacin, ceftazidime, and DNase at subminimal inhibitory concentrations against PAO1 bioiflm. Collectively, our study lays the foundation for further investigation of repurposing meloxicam as a topical antibiofilm agent to treat P. aeruginosa biofilm‐related infections.
p16(INK4a) plays a key role in control of cell cycle progression by negatively regulating the CDK4/6 activity. This study establishes that the p16(INK4a) minimal promoter region required for the transcription factor Sp1 function is mapped at 62 bp upstream of the translation initiation codon. This region is GC-rich and shown to interact specifically with Sp1. siRNA-induced Sp1 silencing resulted in the inhibition of the p16(INK4a) minimal promoter activity. Additionally, by using a promoter sequence-directed siRNA method, we demonstrate that the histone H3 at the GC-rich region in the minimal promoter of p16(INK4a) is hypermethylated, with a concurrent reduction of both the activity of p16(INK4a) promoter and the level of endogenous p16(INK4a) mRNA. Moreover, we show that the specific mutation of the GC-rich region of the minimal promoter resulted in the complete loss of its regulatory activities. We conclude that the region spanning -62 to +1 bp of p16(INK4a) promoter plays a role in p16(INK4a) transcription regulation.
Staphylococcus aureus strains isolated from diabetic foot ulcers (DFUs) have less virulence, but still cause severe infections. Furthermore, hypovirulent S. aureus strains appear to be localized in the deep tissues of diabetic foot osteomyelitis, indicating that the unique environment within DFUs affects the pathogenicity of S. aureus. In this study, the cell-free culture medium (CFCM) of S. aureus strains isolated from DFUs exhibited higher cytotoxicity to human erythrocytes than those isolated from non-diabetic patients with sepsis or wounds. Among these S. aureus strains isolated from DFUs, β-toxin negative strains have less virulence than β-toxin positive strains, but induced a higher expression of inflammatory cytokines. Our study and previous studies have shown that the synergistic effect of phenol-soluble modulin α and β-toxin contributes to the higher hemolytic activity of β-toxin positive strains. However, lysis of human erythrocytes by the CFCM of β-toxin negative strains was greatly inhibited by an autolysin inhibitor, sodium polyanethole sulfonate (SPS). A high level of glucose greatly reduced the hemolytic activity of S. aureus, but promoted the expression of interleukin-6 (IL-6) in human neutrophils. However, 5 mM glucose or glucose-6-phosphate (G6P) increased the hemolytic activity of SA118 (a β-toxin negative strain) isolated from DFUs. Additionally, patients with DFUs with growth of S. aureus had lower level of serum IL-6 than those with other bacteria, and the CFCM of S. aureus strains significantly reduced lipopolysaccharide-induced IL-6 expression in human neutrophils. Therefore, the virulence and inflammatory response of S. aureus strains isolated from DFUs are determined by the levels of glucose and its metabolites, which may explain why it is the predominant bacteria isolated from DFUs.
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