Tale of Twin Bifunctional Second Messenger (p)ppGpp Synthetases and Their Function in Mycobacteria.

M. tuberculosis, an etiological agent of tuberculosis, requires a long treatment regimen due to its ability to respond to stress and persist inside the host. The second messenger (p)ppGpp-mediated stress response plays a critical role in such long-term survival, persistence, and antibiotic tolerance which may also lead to the emergence of multiple drug resistance. In mycobacteria, (pp)pGpp molecules are synthesized predominantly by two bifunctional enzymes-long RSH-Rel and short SAS-RelZ. The long RSH-Rel is a major (p)ppGpp synthetase and hydrolase. How it switches its activity from synthesis to hydrolysis remains unclear. RelMtb mutant has been reported to be defective in biofilm formation, cell wall function, and persister cell formation. The survival of such mutants has also been observed to be compromised in infection models. In M. smegmatis, short SAS-RelZ has RNase HII activity in addition to (pp)Gpp synthesis activity. The RNase HII function of RelZ has been implicated in resolving replication-transcription conflicts by degrading R-loops. However, the mechanism and regulatory aspects of such a regulation remain elusive. In this article, we have discussed (p)ppGpp metabolism and its role in managing the stress response network of mycobacteria, which is responsible for long-term survival inside the host, making it an important therapeutic target.

Vitamin C and its therapeutic potential in the management of COVID19.

COVID19 has emerged as one of the worst pandemics in the history of mankind. Several vaccines have been approved by different government agencies worldwide, but data on their efficacy and safety are limited, and distribution remains a massive challenge. As per WHO, personal immunity is vital for protection against COVID19. Earlier, Vitamin C-mediated pathways have been shown to play critical role in boosting immunity attributed to its antioxidant properties. Recently, the involvement of such pathways in protection against COVID19 has been suggested. The controlled doses of Vitamin C administered through intravenous (IV) injections are being studied for determining its role in the prognosis of COVID19. In this article, we have discussed the potential role of Vitamin C in the management in COVID19 patients and presented recent clinical trials data. Additionally, we have elaborated the possibility of administering Vitamin C through inhalers in order to achieve local high concentration and the challenges of such approach.

The extended (p)ppGpp family: New dimensions in Stress response.

Second messenger (p)ppGpp mediated stress response plays a crucial role in bacterial persistence and multiple drug resistance. In E. coli, (p)ppGpp binds to RNA polymerase and upregulates the transcription of genes essential for stress response while concurrently downregulating the expression of genes critical for growth and metabolism. Recently, the family of alarmone molecules has expanded to pppGpp, ppGpp, pGpp & (pp)pApp as distinct members. These molecules may help in fine-tuning stress responses in different hostile conditions. Do all of these molecules bind to RNA polymerase? Do they compete with each other or complement each other's functions is still not clear. Earlier, others and we have synthesized artificial analogs of (p)ppGpp that inhibited (p)ppGpp synthesis and long-term survival in M. smegmatis and in B. subtilis suggesting that analogs could compete with each other. Understanding the interplay of these molecules will allow deciphering novel pathways that can be potentially subjected to the therapeutic intervention. In this article, we have reviewed newly characterized second messengers and discussed their mode of action. We have also documented the progress made to-date in understanding the molecular basis of regulation of transcription by second messenger ppGpp, pppGpp, and pGpp.