Subinhibitory concentrations of trimethoprim and sulfamethoxazole prevent biofilm formation by Acinetobacter baumannii through inhibition of Csu pili expression [PublishAheadOfPrint]

Acinetobacter baumannii is emerging as a multi-drug resistant nosocomial pathogen of increasing threat to human health worldwide. Pili are important bacterial virulence factors, playing a role in attachment to host cells and biofilm formation. The Csu pilus, assembled via the chaperone-usher secretion system, has been studied in A. baumannii ATCC 19606. Here we show that, in opposition to previous reports, the common lab strain ATCC 17978 produces Csu pili. We found that, although ATCC 17978 is resistant to sulfamethoxazole (Smx) and trimethoprim (Tmp), subinhibitory concentrations of these antibiotics abolish the expression of Csu and consequently a dramatic reduction in biofilm formation in ATCC 17978. Smx and Tmp act synergistically inhibiting the enzymatic systems involved in the bacterial synthesis of tetrahydrofolate (THF), which is required for the synthesis of nucleotides. The effect of these antibiotics was partially relieved by exogenous addition of THF, indicating that Smx and Tmp turn off Csu assembly by inducing folate stress. We propose that, for Acinetobacter, nanomolar concentrations of Smx and Tmp represent a "danger signal". In response to this signal, Csu expression is repressed, allowing biofilm dispersal and escape from potentially inhibitory concentrations of antibiotics. The roles of antibiotics as signalling molecules start to be increasingly acknowledged, which have clear implications for both, the treatment of bacterial diseases, and the understanding of the complex microbial interactions in the environment.

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