Deciphering Rickettsia conorii metabolic pathways: A treasure map to therapeutic targets

Abstract

Indian tick typhus is an infectious disease caused by intracellular gram-negative bacteria Rickettsia conorii (R. conorii). The bacterium is transmitted to humans through bite of infected ticks and sometimes by lice, fleas or mites. The disease is restricted to some areas with few cases but in last decade it is re-emerging with large number of cases from different areas of India. The insight in to genetic makeup of bacterial pathogens can be derived from their metabolic pathways. In the current study 18 metabolic pathways were found to be unique to the pathogen (R. conorii). A comprehensive analysis revealed 163 proteins implicated in 18 unique metabolic pathways of R. conorii. 140 proteins were reported to be essential for the bacterial survival, 46 were found virulent and 10 were found involved in resistance which can enhance the bacterial pathogenesis. The functional analysis of unique metabolic pathway proteins showed the abundance of plasmid conjugal transfer TrbL/VirB6, aliphatic acid kinase short chain, signal transduction response regulator receiver and components of type IV transporter system domains. The proteins were classified into six broad categories on the basis of predicted domains, i.e., metabolism, transport, gene expression and regulation, antimicrobial resistance, cell signalling and proteolysis. Further, in silico analysis showed that 88 proteins were suitable therapeutic targets which do not showed homology with host proteins. The 43 proteins showed hits with the DrugBank database showing their druggable nature and remaining 45 proteins were classified as novel drug targets that require further validation. The study will help to provide the better understanding of pathogens survival and embark on the development of successful therapies for the management of Indian tick typhus.

Keywords: Indian tick typhus; Metabolic pathways; Rickettsia conorii; Therapeutic targets.

Fig. 1

The overall methodology and statistics of the study was depicted in the figure.

Fig. 2

The venn diagram represents the distribution of unique pathway proteins as essential, virulent, resistant and non-homologous to host proteins.

Fig. 3

Subcellular localization of shortlisted unique metabolic pathway proteins of R. conorii. Most of the proteins were localized in cytoplasm (57 %) followed by inner membrane (41 %) and periplasm (2 %).

Fig. 4

Functional classification of 88 shortlisted unique metabolic pathway proteins which will serve as potential therapeutic targets for drug discovery process. The proteins are classified in to six broad functional classes, i.e., Metabolism, Transport, Gene expression and regulation, Antimicrobial resistance, Cell signalling and Proteolysis. (A) represents broad functional class and (B) represents major functional domains present in the unique metabolic pathway proteins.