Abstract
Knowledge about biofilm-associated antibiotic tolerance mechanisms is warranted in order to develop effective treatments against biofilm infections. We performed a screen of a Streptococcus mutans transposon mutant library for mutants with reduced biofilm-associated antimicrobial tolerance, and found that the spxA1 gene plays a role in tolerance towards gentamicin and other antibiotics such as vancomycin and linezolid. SpxA1 is a regulator of genes involved in the oxidative stress response in S. mutans. The oxidative stress response genes gor and ahpC were found to be up-regulated upon antibiotic treatment of S. mutans wild-type biofilms, but not spxA1 mutant biofilms. The gor gene product catalyses the formation of glutathione which functions as an important antioxidant during oxidative stress, and accordingly biofilm-associated antibiotic tolerance of the spxA1 mutant could be restored by exogenous addition of glutathione. Our results indicate that the oxidative stress response plays a role in biofilm-associated antibiotic tolerance of S. mutans, and add to the on-going debate on the role of reactive oxygen species in antibiotic mediated killing of bacteria.
Highlights
Streptococcus mutans normally resides in the mouth where it is part of multispecies biofilms on teeth
In the present study we provide evidence that the antimicrobial tolerance of S. mutans biofilms depends on an oxidative stress response mediated by the SpxA1 protein, which is a transcriptional regulator of several oxidative stress response genes, and is conserved in low-GC Gram-positive bacteria [13]
In this study we show that biofilms formed by S. mutans spxA1 mutant bacteria are significantly more sensitive towards antibiotics such as gentamicin, vancomycin and linezolid than wild-type biofilms
Summary
Streptococcus mutans normally resides in the mouth where it is part of multispecies biofilms on teeth. S. mutans can cause extra-oral infections like bacteremia and infective endocarditis [2] Both dental caries and infective endocarditis are diseases that are associated with biofilm formation [3, 4]. In order to cause infective endocarditis bacteria originating from the oral microflora must enter the blood circulation, and this can occur during professional dental surgery, and through daily routines like tooth brushing and eating [6]. It is only a fraction of the oral microorganisms that have the ability to cause infective endocarditis. S. mutans is part of the viridans streptococci, which include Streptococcus sanguinis, Streptococcus gordonii and Streptococcus mitis, and these bacteria cause 40–60 % of the cases of infective endocarditis, of which S. mutans has been shown to account for approximately one fifth of the cases [5]
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