Imagine a world where a simple cut from a kitchen knife or a sewing needle, leading to an infection, can cause blood poisoning and ultimately death. As bizarre as this may sound, blood poisoning from an open wound was a common cause of death across the world before antibiotics were used to combat such infections. Prior to the discovery of penicillin, infections were treated using ludicrous techniques that involved consumption of heavy metals that were often very painful, cleaning of the wounds by bug eating maggots that often left the patients in agony or other less severe but ineffective methods like consuming garlic, honey, and tree barks. The discovery of penicillin in the UK and its mass production by US pharma giants in the 1940s have changed how humanity fought against deadly infections such as syphilis, pneumonia, plague etc. The ‘antibiotics-era’ saw a drastic increase in life expectancy and a decrease in deaths caused due to infections1. The top three causes of deaths in the US during the early twentieth century were pathogenic infections, whereas now, cardiovascular, cerebrovascular and cancer diseases are the three major causes of deaths2. Several generations of humans have never witnessed how severe and deadly common conditions such as urinary tract infections, pneumonia and childbed fever can be.

But bacteria are smarter than humans. They live on our skin, guts and even control our brains! So naturally, they have also found a way to combat man’s greatest discovery of the 20th century — antibiotics! The antibiotics-era witnessed the industrial and incessant use of antibiotics not just in hospitals or clinics, but also in the livestock industry to boost the production of meat. In developing countries, medical doctors commonly prescribe antibiotics for any kind of infection, including viral! In fact, more than 50% of the currently prescribed antibiotics are for upper respiratory tract viral infections3. This excessive, and often unnecessary use of antibiotics has imposed years of selection pressure on these pathogenic bacteria, enabling them to develop resistance against common antibiotic families like β-Lactams and Macrolides. They develop resistance by clever genetic and biochemical mechanisms involving horizontal gene transfer, efflux pumps et cetera4,5. Compounding to this problem, we have not developed any new antibiotic since the late 1980s that has managed to enter the market6. The speed at which new drugs are discovered remains slower than the rates at which these microbes can evolve around the existing drugs to become resistant and tougher to eliminate. Therefore, we currently find ourselves in a dire situation where even simple procedures such as dental surgeries or childbirth are becoming life threatening. An estimated 1.2 million deaths were predicted to be caused due to anti-microbial drug resistant (AMR) pathogens in 20197. A report by the British government in 2016 estimates that if left unattended, the economic costs of the AMR pathogens would amount to a whopping $100 trillion in the next thirty years8.

So, what are the necessary actions that we need to take to keep up with new variants of AMR pathogens, develop strategies to limit the spread of infections and produce new families of drugs that can take down the evolving bugs? First, it is necessary for institutions across the world to support basic science programs aimed at understanding the cell biology of bacteria and finding efficient ways to commercialize new discoveries. Some of the main scientific challenges that still require extensive research are - how will new generation of drugs enter the bacterium through its impenetrable cell wall, how can human cells bear the toxicity at high doses needed in treatments and how can clinical trials be conducted on drug resistant bacteria? The emergence of AI in drug discovery9 and technological improvements in structural biology10 have steered clear some of the challenges faced during the creation of new treatments. It is important to note that the fundamental science behind understanding the mechanisms of resistance development and inventing new antibiotics are constantly improving, and there are many innovations made in this arena in the last several decades11,12,13.

Second, the reason why there have been no new class of antibiotics in the market lately is because it is not profitable for pharma companies to invest in their research and development. Patients needing antibiotics will recover from an infection within a few days or weeks. Whereas cancer drugs or other lifestyle drugs will be used by patients over a significantly longer period, and therefore will provide more returns on investments. Unless there is a major revamp in business models, profit-driven companies operating in free market capitalist economies will not invest in long-term, high risk and low reward projects such as antibiotic development. This is a classic example of when government interventions can bear fruitful results. Therefore, governments across the world should come together, and provide a monetary and institutional framework to both public and private players to carry out cutting edge translational research in antimicrobial discovery. It is only in the last few years that policy makers and international organizations are noticing the gravity of the situation and are seriously acting towards a solution14. The Fleming fund is one such example of an inter-governmental framework to enable high quality cutting-edge research in AMR pathogens. Given the urgency and importance of AMR infections, more such initiative should be launched especially in low- and middle-income countries where the AMR pandemic will have the most impact. Currently, the available funding programs are concentrated in North America or Western Europe or Japan. Organizations such as BRICS and SAARC should set up committees to monitor the spread of AMR, develop collaborative funding schemes and push for new government policies related to bringing science from bench to bedside.

A more recent and critical development in our understanding of the origin of AMR pathogens is the discovery of antimicrobial agents polluting our environment15. Poor waste management practices in factories manufacturing antimicrobials have resulted in these compounds finding their way into nearby streams and fields. Farm labourers and other workers coming in direct contact with such environments tend to develop drug resistant bacterial infections. Towards this, there needs to be stricter regulations on pharmaceutical industries to treat their effluents. This is particularly a case of concern in developing economies like India that also happen to be the world’s largest generic drug manufacturing hub. A welcome step in this direction is the establishment of cross-country partnership such as the ‘India-UK Tackling AMR in the Environment from Antimicrobial Manufacturing Waste’ program to better understand the roles and effects of environmental discharge from pharma companies.

In addition to the earlier mentioned governmental actions such as revamping policies and creating new institutional frameworks, our society needs to play major a role in combating AMR infections. First, common population needs to be aware about latest good medical practices pertaining to antibiotic use. Recently, in the Indian state of Kerala, a public-private partnership to manage AMR pathogens has led to a successful antimicrobial stewardship16. This program involved revamping medical college curriculum, developing antibiotic clinical guidelines, and conducting workshops for medical doctors across the state to make them aware of accepted practices in tackling AMR infections. Similar programs led by common people should be encouraged in other parts of the world too.

Sadly, a majority of the economic and social burden of the AMR pathogens will be felt in the developing world17. Tackling the AMR infections will require significant technological innovation and comes with economic opportunities. Taking steps towards this will therefore help the socio-economic aspirations of these countries. But a failure to immediately act against this lurking pandemic will entrap our entire humanity to a pre-antibiotic era. If there is something we all have learnt from the devastating COVID-19 pandemic, it is that we need to act far in advance and be prepared to tackle any future pandemic. The spread of AMR pathogens, together with poor health care infrastructure, a collapsing global supply chains and lack of medical awareness, is a hidden catastrophe waiting to explode anytime18.

References:

  1. The treasure called antibiotics, Ann Ib Postgrad Med. (2016); 14(2): 56–57.

  2. Hannah Ritchie and Max Roser (2018) - “Causes of Death”. Published online at OurWorldInData.org.

  3. https://healthyhorns.utexas.edu/HT/HT_antibiotics.html

  4. Hacker, J., and J. B. Kaper. 2000. Pathogenicity islands and the evolution of microbes. Annu. Rev. Microbiol. 54:641-679.

  5. Alekshun MN, Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell. 2007 Mar 23;128(6):1037-50.

  6. Challenges of antibacterial discovery. Clin. Microbiol. Rev. 24, 71–109 (2011).

  7. https://www.ft.com/content/accf1951-48db-40f8-910f-16f66ff5531d

  8. Tackling drug-resistant infections globally: final report and recommendations. The review on antimicrobial resistance chaired by Jim O’Neill, May 2016.

  9. Accelerating antibiotic discovery through artificial intelligence. Commun Biol 4, 1050 (2021). https://doi.org/10.1038/s42003-021-02586-0

  10. Cryo-EM in drug discovery: achievements, limitations and prospects. Nat Rev Drug Discov 17, 471–492 (2018). https://doi.org/10.1038/nrd.2018.77

  11. Front. Microbiol., 09 December 2020 | https://doi.org/10.3389/fmicb.2020.591426

  12. Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E. Nat Commun 10, 2992 (2019). https://doi.org/10.1038/s41467-019-10754-4

  13. Alekshun MN, Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell. 2007 Mar 23;128(6):1037-50. doi: 10.1016/j.cell.2007.03.004.

  14. Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report, World Health Organization, 2021.

  15. Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens. Infection 45, 479–491 (2017). https://doi.org/10.1007/s15010-017-1007-2

  16. A road-map for addressing antimicrobial resistance in low- and middle-income countries: lessons learnt from the public private participation and co-designed antimicrobial stewardship programme in the State of Kerala, India. Antimicrob Resist Infect Control 10, 32 (2021). https://doi.org/10.1186/s13756-020-00873-9

  17. Antibiotic resistance in Africa: ‘a pandemic that is already here’, David Pilling, Financial Times, March 2022.

  18. Antibiotic resistance kills over 1m people a year, says study, Oli Elliott, Alan Smith and Andrew Jack, Financial Times, January 2022.