The Role of the RamA Locus in the Establishment of Antibiotic Resistance and its Potential for Novel Antibiotic Therapy

Klebsiella pneumoniae is a major hospital pathogen which causes a multitude of infections in both immuno-competent and compromised patients. The emergence of multidrug resistant K. pneumoniae has grave implications for public health as options with which to control these organisms are becoming scarce. Antibiotic resistance emerges when bacteria survive the initial drug challenge and undergo mutations. Certain proteins in bacteria facilitate the survival of bacteria under these conditions. One such protein made by K. pneumoniae is the RamA protein. RamA is a regulatory protein that controls genes involved in antibiotic resistance, fitness and virulence. This research aims to understand what role RamA plays in the bacterial cell in allowing survival and subsequent emergence of antibiotic resistance. Understanding of the role of RamA will give insights into strategies bacteria use to survive antibiotic challenge. This information is crucial in combating the emergence and spread of antibiotic resistance.

Transcription factors that control pleiotrophic phenotypes in bacterial metabolism and physiology present a novel opportunity to inhibit microbes on several levels. As such, proteins that confer both an antibiotic resistant phenotype and promote virulence gene expression are particularly attractive drug targets. The RamA protein found in Klebsiella pneumoniae and Salmonella spp. is a transcription factor that plays a role in multidrug resistance and virulence. This project aims to understand the role of RamA in antibiotic resistance through its regulation and expression. The specific aims of the research project are to determine the regulation of the ramA gene and the genes it regulates; to investigate the prevalence of increased ramA gene expression and its contribution to the dissemination and emergence of clonal and non-clonal multidrug resistant populations of Klebsiella and Salmonella spp; and finally to understand the population dynamics of ramA expression in an antibiotic susceptible bacterial population. The study of the role of ramA in the emergence of antibiotic resistance is of critical importance, as unlike most other antibiotic resistance mechanisms, it is not drug specific but rather a response triggered by a host of unrelated compounds. Studying the function of this gene and its products is critical to the understanding of its role in antibiotic resistance, especially in bacteria that are multidrug resistant and which clearly pose a threat to human health.