Antimicrobial Resistance (AMR) among bacterial pathogens is reaching an all-time high and this has been characterised as a ‘silent tsunami’ by the World Health Organization (WHO). India specifically has been identified as a hotspot of emerging antibiotic resistance owing to excessive use to antibiotics in both domestic animals and humans. A careful examination of approaches for countering the multifaceted complex problem of multidrugresistant pathogens is needed, as the rise of antibiotic failure poses a severe threat to global health. There is growing concern that this failure is not solely driven by stable antibiotic resistance but also by a subpopulation of transiently non-growing, antibiotic tolerant bacteria, that are thought to seed relapsing infections. Bacterial pathogens such as Pseudomonas aeruginosa, Salmonella, Shigella, and pathogenic Escherichia coli (Enteropathogenic E. coli and Enterohemorrhagic E. coli) cause life-threatening diseases, particularly in young children and immuno-compromised individuals. Given this predicament, we are investigating health linkages between humans, animals, and their shared environments to embrace the concept of an integrated One Health approach.
Along with infectious disease surveillance, there is a need to study and understand the scale of the crisis raised by AMR. Due to non-availability of information on the magnitude of resistance, the overall resistome and against which drugs, there is a dire need of surveillance of AMR genes in the environment. We are working towards developing capacity to detect AMR at a city-wide level, which is crucial for taking measures to mitigate the problem and avoid the future loss of lives, as well as economic losses.
To date, there has been no successful strategy to ensure that MDR strains can be reverted to an antibiotic sensitive phenotype. In our research plan, we will explore alternate strategies to combat AMR using Natural Products, bacteriophages specific to the pathogenic bacteria and also utilize CRISPRbased genome editing strategies with plasmids and/ or lysogenic phage for sensitizing critical priority Gram negative ESKAPE pathogens such as MDR Pseudomonas aeruginosa to antibiotics. Additionally, these approaches can also be applied to other multi-drug resistant nosocomial pathogens such as Klebsiella pneumoniae, Acinetobacter baumanii as well.
In order to address some these aspects, we have identified novel or partially characterized antibiotic resistance genes by mutation analysis to be targeted in Pseudomonas aeruginosa. We have also explored bacteriophage resistance and innate immune susceptibility in Pseudomonas aeruginosa. PAO1 was treated with AM.P2 phage and phage resistant mutants were successfully isolated. Different strategies were explored to design a plasmid that could be used to create an integrating base editing system in Pseudomonas aeruginosa for reversal of drug resistance. A Tn7 transposon-based integrated CRISPR Base editing system was developed to target ampC/ampR in Pseudomonas aeruginosa PAO1.
Invesigator: Farah Ishtiaq
Collaborators:
Amrita Vishwa Vidyapeetham