Research

1. Bacterial Signal Transduction Modules as Novel Drug Targets-

Bacterial cells sense and respond to their environment by several signaling mechanisms, the most important of which is two-component systems (TCS). The canonical TCS consists of a sensor histidine kinase, and a response regulator. The sensor kinases sense various external signals and in turn get auto-phosphorylated and transmit the signal to the cognate response regulators in a phosphorylation dependent pathway. The phosphorylated response regulators generally function as transcription factors and modulate the expression of several genes (Dmitriev et al., 2011; Biswas and Mohapatra, 2012; Shankar et al., 2015; Khara et al., 2018). Our broad objective in this area is to understand the role of TCS in developing antimicrobial resistance (AMR) in bacterial pathogens. Bacterial species possess tens to hundreds of TCS in their genome, many of which remain to be characterized functionally. As the pathogens engage these signaling modules to sense their surrounding including antibacterial substances, the signaling modules have a role in developing AMR. Therefore, finding a novel way to block the signaling pathway can inhibit the development of drug resistance. The long-term goal is to develop possible intervention methods that target this signal transduction process in bacterial pathogens. This research in the lab is supported by funding from SERB, Govt. of India, and OSHEC, Govt. of Odisha.

2. Epigenetic Regulation of Bacterial Cell Cycle-

Epigenetic mechanisms regulating various physiological activities in the prokaryotic cells are increasingly being appreciated. Methylation of specific bases of the DNA molecule by methyltransferases is the most common epigenetic modification observed in the bacterial cells. This modification of nucleotides adds another level of regulation at the transcription; furthermore, it has a fundamental role in the cell physiological processes such as DNA replication, DNA mismatch repair, and virulence mechanisms in many pathogens. Among the prokaryotic DNA methyltransferases, Dam expressed in the Gammaproteobacteria is the most extensively studied. In contrast to Dam, another DNA methyltransferase CcrM (Cell Cycle Regulated Methylase) has been described in the Alphaproteobacteria, where it plays an important role in the cell cycle regulation of Caulobacter crescentus and Agrobacterium tumefaciens, in the infection process of Brucella abortus, and in the symbiotic mechanism involving Sinorhizobium meliloti etc. Both Dam and CcrM methylate the adenine residue in the respective recognition motifs 5’-GATC-3’ and 5’-GAnTC-3’. Among the several functional differences between Dam and CcrM, the most prominent is the role of the later in cell cycle regulation (Fioravanti et al., 2013; Mohapatra et al., 2014; Mohapatra et al., 2020). Our interest in this area is to understand how DNA methylation plays a role in coordinating several physiological processes in a cell cycle dependent manner using the Alphaproteobacterium model Caulobacter crescentus.