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Structural and Functional Studies of Bacterial Stress Response Mechanisms

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

Antibiotic resistance has been listed as a global concern and one of the greatest threats to human health in the most recent reports by World Economic Forum (Global Risks Report 2014 and 2016) and the World Health Organization (Worldwide country situation analysis, 2015). Before the discovery of the penicillin, there was no effective treatment for infectious diseases such as gonorrhea, tuberculosis, and cholera. Antibiotic discovery made it possible to cure the deadliest infectious diseases, until the bacteria evolved certain survival mechanisms. It is no surprise that all living organisms adopt to ever-changing environmental conditions, as so did bacteria. By either acquiring genetic resistance or expressing the persister phenotype, bacteria can survive most antibiotics, if not all.

The bacterial persistence and antibiotic resistance have been linked to type II toxin antitoxin systems and (p)ppGpp mediated stringent response, respectively. In this study, we present effective purification protocols for RelA from F. tularensis, and nanobody-mediated crystallography. Later on, we report the structure of a small alarmone synthetase, RelP, from a major human pathogen S. aureus including both pre- and the post catalytic states. The structure of RelP provides detailed information on the synthesis of the alarmone in structural basis, at the same time points out to the importance of metal ions for the enzyme regulation. Next, an initial low-resolution cryo-EM model of a SAS enzyme fused to an RNase HII domain is presented.

Finally, a full-length structure of the type II toxin-antitoxin complex HicAB from E. coli is explained. The structures of the HicAB complex and the HicB antitoxin should fulfill the recent literature by providing a full-length wild type complex with the antitoxin adopting a helix-turn-helix DNA-binding domain. The models of both structures should explain the binding mode of DNA, and how these toxin-antitoxin modules can regulate their transcription.
Antal sider200
StatusUdgivet - 30 aug. 2018

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