PneumoCompetence · Unravelling the mechanisms of competence induction by antibiotic stress in Streptococcus pneumoniae

Unravelling the mechanisms of competence induction by antibiotic stress in Streptococcus pneumoniae

Despite the introduction of several vaccines, the human pathogen Streptococcus pneumoniae remains one of the leading bacterial causes of mortality worldwide, killing 1 million of children each year. In developed countries, the rise of multi-drug resistance in S. pneumoniae during the last decade is a serious cause of concern, since the patient is more likely to require hospitalization consuming high health resources, and increasing the risk of death. The main mechanism by which S. pneumoniae acquire and spread antibiotic resistance is by activation of the competence state that allows the uptake of exogenous DNA. Strikingly, competence is induced by several antibiotics, but the molecular mechanisms driving competence development are poorly understood. Using several approaches, I identified several common antibiotics that induce competence and thereby promotes the acquisition and spread of antibiotic resistance. One particular interesting case is the effect of the betalactamase inhibitors (clavulanic acid and tazobacta) not active against Streptococcus pneumoniae (pneumococcus does not produce betalactamases), but still able to promote competence. Clavulanic acid has no antimicrobial activity using clinical concentrations, and is administered with amoxicillin (which alone is not able to induce competence) for the treatment of infections caused by bacterial producers of betalactamases, mainly Haemophillus influenzae, Moraxella catarrhalis or Pseudomonas aeruginosa. This is a severe cause of concern because the combination of amoxicillin-clavulanic acid is the second most antibiotic sold during the last years (Weber F et al, ISM Health Database 2016), and is included in clinical guidelines and recommendations for the treatment of respiratory infections (i.e. bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis), in most of which S. pneumoniae is the main etiological agent (19). Hence, the combination of amoxicillin-clavulanic acid for the treatment of pneumococcal infections has no extra benefit but promotes the acquisition of antibiotic resistance; thereby, the guidelines should be reviewed and, when the aetiological agent of the infection is S. pneumoniae, the patient should be treated with amoxicillin alone instead to the combination with clavulanic acid. In parallel, I have identified small molecules inhibitors of the competence and transformation processes, which could help for future novel treatment strategies against bacterial infections and the mitigation of the spread of antibiotic resistance.

Data: CORDIS, © European Union