Projects / Programmes
Molekulski mehanizem sprožitve proteazne aktivnosti bakterijskega represorja LexA (Slovene)
| Code |
Science |
Field |
Subfield |
| 4.06.04 |
Biotechnical sciences |
Biotechnology |
Microbe biotechnology |
| Code |
Science |
Field |
| 2.11 |
Engineering and Technology |
Other engineering and technologies |
Researchers (14)
Organisations (1)
Significance for science
The SOS response is in bacteria induced by stress provoked by DNA damage and arrest of DNA replication. Even though the SOS response was first described in 1974, the molecular mechanisms involved in induction of the response are still unresolved. Recent studies have revealed that the SOS response controls, besides DNA repair, also the development and dissemination of antibiotic resistance. Among the most problematic are Enterobacteria, Staphylococcus aureus and C. difficile. The latter has been designated by the media a "superbacteria", and with regard to mortality already surpasses methicillin resistant S. aureus (MRSA). The key regulators of the SOS response are protein RecA, the activator and the repressor, LexA. Our work was first to resolve the structure of the DNA bound LexA protein and that of LexA enabling self cleavage which is required for induction of the SOS response. Our results have provided important insight into the SOS system upgrading the current model of the SOS response. In collaboration with dr. Maja Rupnik, we were first to initiate studies of the SOS resposne of C. difficile. The latter is one of the most common causative agents of nosocomial intestinal infections. As we showed that, the E. coli RecA* protein, induces self-cleavage of LexA or DinR (C. ciffficile homolof of LexA) our results indicate that, the SOS response is widely conserved among bacteria. Employing in silico analysis, we were first to determine 15 potential DinR operator sites in the C. difficile genome. The operator sites were confirmed employing SPR and subsequently, a DinR DNA binding motif was constructed for C. difficile.
Significance for the country
Successful treatment of bacterial infections and prevention of the dissemination of antibiotic resistances requires the use of efficient antimicrobial agents. Due to the prevalence of antibiotic resistance determinants, in Slovenia as well as elsewhere, consecutive treatment with several different antibiotics as well as with combinations of antibiotics has become frequent. More frequent is hospitalization which markedly increases health care costs, affects the quality of life and additionally endangers other hospitalized patients. A marked increase in mortality due to antibiotic therapy associated infection with Clostridium difficile, provoking pseudomembranous colitis, has also been established. Urgently needed are new approaches and new targets of antimicrobial agents. Discovery and use of substances which inhibit mechanisms provoking antibiotic resistance, as for example the SOS system, will also prolong the efficacy of clinically significant traditional antibiotics. Novel approaches such as, crystalography and modelling of target proteins, allow for more rapid and efficient quests for appropriate targets and their inhibitors. The results of our research project elucidate the molecular mechanism of self cleavage of the LexA protein. On the basis of our research and in collaboration with the Faculty of Pharmacy, new antibiotic substances which inhibit the SOS response are already being developed and tested. Additionally, our results were published in a journal ranking at the top of the field (Nucleic Acids Research, IF=8,026), placing Slovene science on a global scale, at a level comparable with the best.
Most important scientific results
Annual report
2009,
2010,
2011,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2009,
2010,
2011,
final report,
complete report on dLib.si
