Research Article: Expression of Streptococcus pneumoniae Bacteriocins Is Induced by Antibiotics via Regulatory Interplay with the Competence System

Date Published: February 3, 2016

Publisher: Public Library of Science

Author(s): Morten Kjos, Eric Miller, Jelle Slager, Frank B. Lake, Oliver Gericke, Ian S. Roberts, Daniel E. Rozen, Jan-Willem Veening, Andreas Peschel.


Pneumococcal bacteriocins (pneumocins) are antibacterial toxins that mediate intra-species competition within the human host. However, the triggers of pneumocin expression are poorly understood. Using RNA-sequencing, we mapped the regulon of the pneumocin cluster (blp) of Streptococcus pneumoniae D39. Furthermore, by analogy with pneumococcal competence, we show that several antibiotics activate the blp-genes. Using real-time gene expression measurements we show that while the promoter driving expression of the two-component regulatory system blpR/H is constitutive, the remaining blp-promoters that control pneumocin expression, immunity and the inducer peptide BlpC, are pH-dependent and induced in the late exponential phase. Intriguingly, competence for genetic transformation, mediated by the paralogous ComD/E two-component quorum system, is induced by the same environmental cues. To test for interplay between these regulatory systems, we quantified the regulatory response to the addition of synthetic BlpC and competence-stimulating peptide (CSP). Supporting the idea of such interplay, we found that immediately upon addition of CSP, the blp-promoters were activated in a comD/E-dependent manner. After a delay, blp-expression was highly induced and was strictly dependent on blpRH and blpC. This raised the question of the mechanism of BlpC export, since bioinformatic analysis showed that the genes encoding the putative exporter for BlpC, blpAB, are not intact in strain D39 and most other strains. By contrast, all sequenced pneumococcal strains contain intact comAB genes, encoding the transport system for CSP. Consistent with the idea that comAB mediate BlpC export, we finally show that high-level expression of the blp-genes requires comAB. Together, our results demonstrate that regulation of pneumocin expression is intertwined with competence, explaining why certain antibiotics induce blp-expression. Antibiotic-induced pneumocin expression might therefore have unpredictable consequences on pneumococcal colonization dynamics by activating genes that mediate intra-specific interference competition.

Partial Text

Streptococcus pneumoniae is a Gram-positive opportunistic pathogen that resides in the human nasopharynx. Pneumococci can cause invasive and non-invasive infections to which children, the elderly and the immunocompromised are particularly susceptible. The carriage rate of S. pneumoniae in the human population can be very high. Up to 80% of children under the age of 5 are colonized [1], and colonization with multiple strains simultaneously is widespread. Competition between strains in the human nasopharynx during co-colonization has important implications for the epidemiology of the pneumococcus, potentially influencing strain prevalence, serotype distributions and disease progression.

We and others recently discovered that exposing the human pathogen S. pneumoniae to antibiotics that either stall replication forks [16] or increase the misfolding of proteins [17] can induce competence, leading to increased transformation rates [15,16]. Here we show that exposing S. pneumoniae to the same types of antibiotics can also activate expression of the blp genes, encoding antimicrobial peptides as well as genes necessary for self-immunity, processing, transport and regulation. Because blp bacteriocins are involved in pneumococcal inter-strain competition [4], antibiotic exposure therefore has the potential to indirectly modify competitive interactions among coexisting pneumococcal strains within the human nasopharynx.




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