Advanced Glycation End Products Enhance Biofilm Formation by Promoting Extracellular DNA Release Through sigB Upregulation in Staphylococcus aureus

Abstract

Bacterial biofilms do serious harm to the diabetic foot ulcer (DFU) because they play a crucial role in infection invasion and spread. Staphylococcus aureus , the predominant Gram-positive bacteria in diabetic foot infection (DFI), is often associated with colonization and biofilm formation. Through biofilm formation tests in vitro , we observed that S. aureus bacteria isolated from DFU wounds were more prone to form biofilms than those from non-diabetic patients, while there was no difference in blood sugar between the biofilm (+) diabetics (DB+) and biofilm (-) diabetics (DB-). Furthermore, we found that advanced glycation end products (AGEs) promoted the biofilm formation of S. aureus in clinical isolates and laboratory strains in vitro , including a methicillin-resistant strain. Analysis of biofilm components demonstrated that the biofilms formed mainly by increasing extracellular DNA (eDNA) release; remarkably, the S. aureus global regulator sigB was upregulated, and its downstream factor lrgA was downregulated after AGE treatments. Mechanism studies using a sigB -deleted mutant (Newman-Δ sigB ) confirmed that AGEs decreased expression of lrgA via induction of sigB , which is responsible for eDNA release and is a required component for S. aureus biofilm development. In conclusion, the present study suggests that AGEs promote S. aureus biofilm formation via an eDNA-dependent pathway by regulating sigB . The data generated by this study will provide experimental proof and theoretical support to improve DFU infection healing.

3D scaffolds in the treatment of diabetic foot ulcers: New trends vs conventional approaches

“…In a long-term study conducted between 2008 and 2015, Escherichia coli and Staphylococcus aureus were the two most common bacteria found to infect diabetic wounds (Zubair and Ahmad, 2019). This is supported by more recent findings in where biofilms of S. aureus have been found to be promoted by AGEs, which are increased in diabetic patients (Xie et al, 2020).…”

Staphylococcus aureus Biofilm Inhibiting Activity of Advanced Glycation Endproduct Crosslink Breaking and Glycation Inhibiting Compounds

“…This discrepancy suggests that AGE-induced biofilm formation may be ica- independent, which would explain the lack of efficacy. We have observed a significant increase in extracellular DNA released by S. aureus in response to glucose-keratin exposure (data pending publication), and it has been independently reported that S. aureus eDNA release regulators are promoted by AGE exposure [ 17 ]. Thus, the eDNA dominant biofilm phenotype may be more resistant to ascorbic acid.…”

“…It is speculated that the accumulation of AGEs in the epidermis may play a role both in the etiology of disorders such as AD and dysbiosis of the skin microbiome. It has been reported that glycated proteins enhance S. aureus biofilm formation [ 17 , 18 ], which may increase its potential for pathogenicity. Biofilm confers antibiotic resistance [ 19 ], protects resident bacteria from host immune responses such as phagocytosis [ 20 ], and perpetuates the dominance of S. aureus on AD skin [ 21 ].…”

The infection characteristics and autophagy defect of dermal macrophages in STZ‐induced diabetic rats skin wound Staphylococcus aureus infection model

“…DFI is a severe, common, and costly complication of diabetes, featured by wound healing and infection clearance disorders. As the most common Gram‐positive Cocci in DFI, S. aureus infection and biofilm formation 20 are frequently found in diabetic chronic foot wounds with poor patients outcomes. However, the exact reasons for the prolonged infection of S. aureus of DFI are still unclear 21,22 .…”