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.
Team
Arati Ramesh, Farah Ishtiaq, Shivranjani C Moharir, Mansi Malik
Activities:
- RNA Therapeutics for Targeting Pathogenic UPEC and Pseudomonas aeruginosa
- Enabling Early Diagnosis of Antimicrobial Resistance in Patients Suffering from Infectious Diseases
- Surveillance for Antimicrobial Resistance Genes in Wastewater
- Understanding the Antimicrobial Resistance Landscape through Wastewater-Based Epidemiology from Open Drainage Systems
- Surveillance of AMR Pathogens and Biomarkers from Clinical Samples
The AMR problem is where disease-causing microbes (bacteria, fungi, and viruses) are becoming less and less susceptible to existing antibiotics. This has resulted in the increased use of some of the most potent antibiotics ever known. One of the approaches needed to address the AMR problem would be to develop novel therapeutics that microbes have not been exposed to thus far. Along these lines, our team seeks to develop novel therapeutic oligonucleotide molecules, designed to target select aspects of microbial physiology. Such Antisense Oligonucleotide (ASO) therapy is designed to either directly kill the microbe (acting as a new antibiotic) or increase its susceptibility towards existing antibiotics (repurposing obsolete antibiotics).
Carrier groups (such as cell-penetrating peptides or lipids) conjugated to oligonucleotide derivatives (such as peptide nucleic acid, locked nucleic acid, morpholino oligos, etc) are used to block the synthesis of essential proteins in the microbe. We are further evaluating the effects of these therapeutic oligos on microbial growth, organization into biofilms, pathogenicity, virulence and resistance to conventional antibiotics. To enable this approach we have set up a BSL-2 level laboratory with three of the six ESKAPE pathogens that are of utmost priority in the Indian AMR context. Initial testing of therapeutic oligos against UTI-causing bacteria and Staphylococcus aureus, a common cause of respiratory infections, skin infections, and abscesses show promising results, both for developing novel antibiotics and for repurposing existing antibiotics.
We are setting up RNA therapeutics against pathogenic UPEC and Pseudomonas. Our aim is to develop highly-specific Oligos/LNAs/PNAs that target select mRNAs in pathogenic bacteria, making them susceptible to antibiotics. This approach will allow us to develop RNAs as new antimicrobials for safely & effectively combating AMR.
Investigator: Arati Ramesh
One of the biggest challenges faced by the medical community is the early detection of the antimicrobial resistance profile of the disease-causing organism. Conventional methods to identify germs and their antibiotic susceptibility take several days, in which time patients can only be treated with broad-spectrum antibiotics, which may not have any effect on the specific infection. This is not only dangerous for the patient but also contributes heavily to increased antibiotic usage and the resultant AMR problem. All efforts must be made to diagnose infectious agents early, along with the ability to predict which antibiotics would be best for treatment.
To enable this, we are investigating the use of known chemical probes that report on the form and function of the bacterial plasma membrane. We seek to establish reliable fluorescence signatures from the probes, that could help distinguish resistant microbes from susceptible ones, under specific antibiotic exposure. Unlike the conventional culture method, this approach uses significantly less cells and does not require several days of growth. Hence, this would be a potential way to detect specific antibiotic resistance early, allowing timely intervention.
Investigator: Arati Ramesh
Climate change and health are inextricably linked with urban wastewater. Water security is an imminent issue in India. Water scarcity and the reduced availability of agricultural water have spurred increased interest in the use of recycled irrigation water. There is concern that antibiotic resistance genes (ARGs) persisting in recycled irrigation water could potentially contribute to the growing overall public health challenge of increasing rates of antibiotic-resistant bacterial infections. Bengaluru is the third largest city (~11 million inhabitants) in India with an efficient sewage network of 28 STPs that processes ~1142.5 million liters per day (MLD) of wastewater. Each STP follows a water treatment technology depending on the quality of raw sewage to make the treated water reusable.
Investigator: Farah Ishtiaq
We are working on understanding the antimicrobial resistance landscape in the city of Hyderabad, Telangana, through wastewater-based epidemiology.
Samples are collected once a month, from the 18 locations along open drains that were identified for the SARS-CoV-2 surveillance. The wastewater is analysed for the resistant pathogens, the antimicrobial resistant genes, the resistant drug classes, and mechanisms conferring resistance, through metagenomics approach.
We are conducting spatiotemporal surveillance of wastewater for identifying the antimicrobial resistance (AMR) genes and associated biomarkers.
Investigator: Shivranjani C Moharir
We have initiated work towards understanding the prevalence of AMR by detecting the pathogens, crucial biomarkers and antimicrobial resistant genes (ARGs) from clinical samples.
We are developing q RT-PCR based assays for rapid, accurate, and low-cost detection. Next-generation sequencing (NGS) approaches shall also be employed to understand the changing AMR landscape of the city.
We are developing qRT-PCR assays for early diagnosis and surveillance of priority AMR pathogens, Antibiotic resistance genes (ARGs) and respective biomarkers from clinical samples. We have filed a provisional patent for inhouse-developed q RT-PCR assay, a Fever Panel. The assay was validated using a mix of several clinical samples.
We have initiated genomic surveillance to determine interplay between priority pathogens and ARGs from clinical samples.
Investigator: Mansi Malik
Collaborators:
Bangalore Baptist Hospital, Bengaluru
Aster CMI Hospital, , Bengaluru
Anand Neuberg Diagnostics Laboratory, Bengaluru
All India Institute of Medical Sciences, Bhopal
ICAR – National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Bengaluru