Abstract
New antibacterial compounds, preferentially exploiting novel cellular targets, are urgently needed to fight the increasing resistance of pathogens against conventional antibiotics. Here we demonstrate that Carolacton, a myxobacterial secondary metabolite previously shown to damage Streptococcus mutans biofilms, inhibits planktonic growth of Streptococcus pneumoniae TIGR4 and multidrug-resistant clinical isolates of serotype 19A at nanomolar concentrations. A Carolacton diastereomer is inactive in both streptococci, indicating a highly specific interaction with a conserved cellular target. S. mutans requires the eukaryotic-like serine/threonine protein kinase PknB and the cysteine metabolism regulator CysR for susceptibility to Carolacton, whereas their homologues are not needed in S. pneumoniae, suggesting a specific function for S. mutans biofilms only. A bactericidal effect of Carolacton was observed for S. pneumoniae TIGR4, with a reduction of cell numbers by 3 log units. The clinical pneumonia isolate Sp49 showed immediate growth arrest and cell lysis, suggesting a bacteriolytic effect of Carolacton. Carolacton treatment caused a reduction in membrane potential, but not membrane integrity, and transcriptome analysis revealed compensatory reactions of the cell. Our data show that Carolacton might have potential for treating pneumococcal infections.
Highlights
Which occurs several hours after Carolacton treatment at low pH only[10], is a secondary effect that might be unique to this species due to the strong acidification of mutans streptococci within mature biofilms[13]
For the first time we report on the physiological effect of Carolacton on the clinically relevant human pathogen S. pneumoniae
We show that growth inhibition by Carolacton occurs for clinical isolates as well as for the virulent laboratory strain TIGR4 and appears to be independent of the serotype
Summary
Which occurs several hours after Carolacton treatment at low pH only[10], is a secondary effect that might be unique to this species due to the strong acidification of mutans streptococci within mature biofilms[13]. To investigate these hypotheses and to understand the mode of action of Carolacton in more detail, we studied the response of S. pneumoniae to Carolacton and compared it with that of S. mutans. Cell death of S. mutans biofilm cells has been shown to be dependent on the eukaryotic-like serine/threonine protein kinase (eSTK) PknB10 and the regulator of cysteine metabolism CysR20 Their homologues in S. pneumoniae TIGR4 were deleted and their response to Carolacton determined. The inhibition of growth of S. pneumoniae by Carolacton shows the characteristics of bactericidal and in some cases even bacteriolytic antibiotics
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