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Influence of a nisin-biogel on virulence factors expression by Staphylococcus aureus isolates from Diabetic Foot Infections
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Resumo(s)
Diabetic Foot Ulcers (DFUs) constitute a favorable environment for colonization by opportunistic
pathogens, and Staphylococcus aureus is the most frequent species isolated from DFUs. Due to
the increasing dissemination of antibiotic-resistant strains, including S. aureus, antimicrobial
peptides (AMPs) have been recognized as promising candidates for treating resistant bacterial
infections. In this study, the AMP nisin had been combined with the natural polysaccharide guar
gum to create nisin-biogel, to be evaluated as a new therapeutic approach to Diabetic Foot
Infections (DFIs). In in vivo infections, bacteria may be exposed to a decreased effective
concentration of antimicrobial agents, referred to as subinhibitory concentrations (sub-MICs).
Sub-MICs of antimicrobial agents may lead to changes in bacteria metabolism, namely in biofilm
formation ability and virulence genes expression. We analyzed nisin-biogel sub-MICs effects on
six different S. aureus clinical isolates, including: (1) multiplication rate by determining optical
density at 600 nm; (2) virulence gene expression, including of genes encoding for staphylococcal
protein A (spA), coagulase (coa), clumping factor A (clfA), autolysin (atl), intracellular adhesin A
(icaA), intracellular adhesin D (icaD) and the accessory gene regulator I (agrI), by relative
quantitative RT-PCR; (3) biofilm formation by a microtiter technique; (4) Coa production using
rabbit plasma; and (5) SpA release using a specific ELISA. Nisin-biogel sub-MICs contributed to
a decrease in bacteria multiplication in a strain-dependent and dose-dependent manner, not
influencing the typical sigmoidal pattern. A decrease on AgrI, Atl and ClfA mRNA expression, and
a trend to increase SpA, Coa, IcaA and IcaD mRNA expression were observed in the presence
of nisin-biogel at sub-MICs. The biofilm-forming ability of S. aureus clinical isolates exhibited a
trend to increase in the presence of nisin-biogel at 1/4 and 1/8 MIC, whereas a concentration
corresponding to 1/2 MIC had no effect on biofilm formation. Nisin-biogel at sub-MICs did not
influence significantly coagulase production. Regarding SpA production, nisin-biogel at sub-MICs
exhibited a trend to decrease the amount of SpA produced in a dose-dependent manner. These
results highlight the importance of optimizing antimicrobial biogel doses before proceeding to in
vivo trials, not only to obtain a maximal antibacterial effect but also to reduce the risk for
upregulation of virulence factors and, consequently, undesirable effects on the treatment of DFIs.
Descrição
Palavras-chave
Diabetic Foot Infections Staphylococcus aureus Nisin-biogel Subinhibitory concentrations Virulence-related factors