Disease-causing microbes such as bacteria and viruses developing resistance to the drugs that are meant to kill them is a global, growing health issue. In time, it could dwarf the Covid-19 pandemic in its ability to destroy lives. In a 2015 publication called Global Action Plan on antimicrobial resistance, the World Health Organization gave a stern warning: the world is heading towards a post-antibiotic era in which common infections could once again kill.

 The problem is getting worse because of hospital-acquired infections. And, global warming is known to increase the spread of infectious diseases. 

The conundrum is this: pathogens develop drug resistance and we need to find newer drugs against which they have no defence. But pharma companies are not investing in anti-infectives research because the returns are low. The problem appears to be intractable, but some pathways to deal with them are emerging. 

The first, of course, is to develop newer drugs, or newer classes of drugs.  One good candidate is antimicrobial peptide (AMP), which are peptides that attach themselves to the body of the pathogen and prevent it from entering our cells (See Quantum dated January 9).  

Another drug candidate is ‘bacteriophages’. These are viruses that get into the bacteria and lyse them — break them open inside-out. Bacteriophage therapy has great potential as an alternative to antimicrobials. “Optimal conditions of phage use, including their concentration, the time and sequence of administration and their combination with the appropriate antibiotics, are likely to establish the effectiveness and reliability of this medicine,” says a 2021 scientific paper published in Pharmaceuticals.  

Dr Subramanian Swaminathan, Director, Infectious Diseases, Gleneagles Global Health City, Chennai, tells Quantum that phage therapy is very old, which was given up in the 1940s after antibiotics burst upon the medical scene. Each bacterium has a phage enemy, so you first need to find out which bacterium is causing the disease in order to bring the matching enemy to kill it. This meant need for very personalised treatment. On the other hand, antibiotics could act on a range of bacteria. Thus, in came antibiotics; phage therapy was shelved. But now, the phages are coming back, because “we are running out of antibiotics”, notes Swaminathan. “We are now developing infections which are almost impossible to treat”.  

Out of sheer desperation the world is turning to phages. However, phages have their own ethical and safety considerations. “While it has been tried and tested, it may not be a long-term solution as bacteria can evolve resistance to bacteriophages too,” notes Dr Shankar Manoharan of the Department of Bioscience and Bioengineering, IIT Jodhpur. Also, clinical trials of bacteriophage therapy of bacterial infections are still at an early stage. However, a lot of research is taking place at a frenetic pace in research laboratories. 

Deeper approach 

While finding newer medicines that kill drug-resistant pathogens is one approach to fight AMR, researchers are also looking for a solution at a deeper level. They are trying to figure out how the pathogens are developing resistance, so that the pathways could be blocked. 

For instance, Dr Manoharan’s lab is working on a hospital-associated pathogen, Klebsiella pneumoniae. (K.pneumoniae is one of the six ‘problem’ microorganisms grouped under the acronym ESKAPE, for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter bacteria.) 

In collaboration with AIIMS, Jodhpur, Manoharan is working on genome sequencing of highly drug-resistant clinical isolates of K.pneumoniae “to understand the mechanisms behind the resistance.”  

Similarly, Dr Sandhya Ganesan, a researcher at the Indian Institute of Science Education and Research (IISER), Trivandrum, is working on understanding ‘host-pathogen interaction’. Some pathogens enter a host (our) cell and disarm the immune system by secreting certain proteins. A better understanding of this mechanism would help in stopping it. Ganesan aims to use bacterial pathogens to “understand fundamental principles of cell-intrinsic defence and immune dysregulation that drive pathogenesis.” The goal is to identify common and distinct themes in host defence using various infectious disease models. 

Ganesan’s work falls broadly under the theme ‘host-based therapies’. It involves the use of ‘interferon signalling pathways’, she told Quantum. Interferons are a type of protein released by our cells when a virus enters the cell’s vicinity and are a part of the ‘cytokine family’. Essentially, Ganesan’s work takes the same approach as vaccines — teaching the body to develop an arsenal and be ready for an attack. 

Yet, another approach is to go further deeper and prevent AMR. These include technologies that can differentiate between viral and bacterial infections, limiting the unnecessary prescription of antibiotics, notes Manoharan. Yet another strategy is for proper disposal of antibiotics and antibiotic-contaminated material, to prevent environmental contamination and the emergence of AMR. 

Thus, there are plenty of options bubbling in lab beakers; one or more of them should work. But the fundamental question is, how to get the pharma industry interested in antimicrobials. “Bioprospecting antibiotics is difficult, expensive and takes time,” says Manoharan, pointing out that the industry would step in only when it sees promise. “Research into antimicrobials by a few pharma companies is not going to help us in the long run,” feels Manoharan. “We need to amplify the search for new antimicrobials by several-fold.” He believes the way to do that is the method adopted by TinyEarth, which gets thousands of students to study local soil microbes, identify pathogen-inhibiting isolates, share the samples for genomic analysis and then identify antibiotic compounds to combat the “resistance crisis”. In other words, a mass movement. 

Govt concerned 

The government of India is aware and concerned. A National Action Plan on containment of Antimicrobial Resistance (NAP-AMR) has been on since April 2017, under which an AMR Surveillance Network, comprising 30 tertiary care hospitals, has been set up “to generate evidence and capture trends and patterns of drug-resistant infections in the country.”  

The government has been coming out periodically with calls for proposals for tackling various aspects of the problem. One such call, for developing rapid diagnostics, just closed last month. India too is getting ready for a long battle of attrition with the doughty microbes.