This article is the first of a two-part essay on antibiotic resistance. The second part is here.
A major challenge in medicine and the biomedical sciences today is the problem of antibiotic resistance, the phenomenon by which agents of infectious diseases – bacteria being most relevant to this article – no longer respond to treatment with the ‘miracle drugs’. Let’s understand this phenomenon by tracing the roles of infectious diseases in human history; our approaches to understanding and treating them over millennia; the recent use and abuse of antibiotics and the resultant spread of antibiotic resistance; the antiquity of antibiotics in natural environments and the inevitability of resistance; and the way forward.
Infectious diseases in human history
Infectious diseases have kept a check on humanity for many thousands of years. The explosive increase in human population densities consequent to the development of agriculture, and later the organisation of societies into city states, would have caused a rapid spread of contagion. One might even go the distance of proposing that the ability to multiply and spread within such highly dense populations by causing disease would have favoured the evolution of virulence in some bacteria. The real picture is probably more complicated than this simple-minded view, but we are probably not entirely off the mark.
There is evidence that a millennium before the year 0, the Egyptian pharaoh Rameses V might have had smallpox, a deadly viral disease which has now been famously eradicated. The Ayurvedic treatise Charaka samhita and the contemporaneous medical work attributed to the Greek Hippocrates describe tuberculosis as sosa/rajayaksma and pthisis respectively around 500 BCE to the first century CE; this is a bacterial disease of much interest today. They also refer to leprosy, another bacterial disease caused by an organism that likely shared a common ancestor with the bacterium that causes tuberculosis. Both these works also refer to intermittent fevers, typical of different forms of malaria, which is neither of bacterial or viral origin but caused by a protozoan.
The Roman Empire, with its unprecedented range and population, was repeatedly challenged by the plague, another bacterial disease which attracted much attention in India after a highly publicised outbreak in Surat in the 1990s. The plague wrecked Europe in the 14th century, leaving traces of devastation from its origin in China through the major centres of civilisation en route to Europe, leading to the moniker “The Black Death”. It has been suggested that this plague might have played a role in introducing societal transformations that resulted in the Renaissance. It is believed in that “ring-a-ring-a roses”, the popular playful nursery rhyme, was in fact motivated by the morbid symptoms of children afflicted with the plague, and we all fall down … dead. In more recent centuries, there have been cataclysmic epidemics and pandemics of bacterial pneumonia and cholera. Today, we talk about the dangers posed by various respiratory viruses and multi-drug resistant bacteria!
Despite being very selective in its cataloguing of historical epidemics, this list should serve to highlight the long-standing coexistence of humans and infectious diseases, and the attendant meeting of challenges posed to one by the other’s biological setup.
Understanding of infectious diseases over millennia
Though mankind has been beset by infectious diseases for long, an understanding of their pathologies is recent. Hippocrates and the ayurvedic physicians of similar vintage were pioneers in largely divorcing the cause of diseases from supernatural forces. However, their theories of disease as manifestations of disturbances in certain fluid balances, which can be influenced by external factors such as the weather and diet, while ahead of their times, are too simple given what we know today. That said, irrespective of the validity of their theories of pathology, these physicians must have practised effective control measures against infectious diseases in light of the evidence that they could successfully perform surgeries. Nevertheless, they did not anticipate the germ theory of disease, which was to flower 2,000 years after their times.
The idea that germs cause disease was promulgated in Europe by an Italian called Girolamo Fracastaro, who proposed in the middle of the 16th century that diseases are caused by contact with certain particles that spread through the air. In the century that followed, the theory of spontaneous generation of certain life forms from nothing was refuted by Francisco Redi; and microscopes were used to observe and describe microorganisms as “animalcules” by Antonie van Leuwenhoek, the father of microbiology.
In 1767, in a book/essay with an impressively long title (“An account of the manner of inoculating for Small Pox in the East Indies with some observations on the practice and mode of treating that disease in those parts”) Holwell describes how certain Brahmins in Bengal “inoculate” local residents with a mixture comprising the pus derived from individuals who had suffered from smallpox the year before. This inoculation, a precursor to the present-day vaccination, was performed before the onset of seasonal smallpox epidemics, and might have been in practice in India from around 1,000 AD. It appears that these practitioners did have a germ theory of disease in mind and argued that contagious diseases were caused by “multitudes of imperceptible animalculae floating in the atmosphere … (which) return at particular seasons in greater or lesser numbers … (and) pass and repass in and out of the bodies of all animals in the act of respiration”.
In the mid-19th century, the works of Ignaz Semmelweis and John Snow identified material sources of puerperal fever and of a cholera outbreak respectively. These findings helped develop simple measures, such as disinfection of hospital workers’ hands with chlorine and the sealing of water wells suspected to originate an infection, to contain these diseases. Earlier, Agustino Bassi had identified a ‘vegetable parasite’ as the source of an infection that was devastating the silkworm industry.
Despite these early studies, formal investigations of the link between “germs” and disease came about in the late 19th century due to Louis Pasteur and Robert Koch. Koch’s postulates on rigorously establishing a link between a germ and a disease is still relevant today, and has recently (about 30 years ago) been expanded into the “molecular Koch’s postulates” by Stanley Falkow at Stanford University. The book Microbe Hunters, written by Paul de Kruif in 1926, is a must-read for anyone interested in human discoveries of infectious diseases.
Containment of infectious diseases in the pre-antibiotic era
Treatment of infectious diseases in the pre-germ theory age appears to have depended on various herbal concoctions. In ancient Ayurveda and Hippocrates’ time, the idea that these diseases were caused by disturbances in certain “humours” meant that interventions were developed that were believed to reverse these disturbances.
In the Abbasid Caliphate’s (8th to 13th century) capital city of Baghdad, which was in an intellectual ferment during this period, quarantine procedures were adopted for containing infectious diseases. Several hundred drug formulations were described by Ibn Sina in Baghdad, the Latin translation of whose works were used as medical textbooks in Europe for close to 500 years. The ninth century Anglo-Saxon text Leechbook of Bald describes recipes for treating certain infectious diseases; we will return to this later.
Being an anti-malarial means artemisinin, whose discovery led to the 2015 Nobel Prize in medicine, is not quite an antibiotic in the sense the term is used today to refer to anti-bacterials. Nevertheless, the herb from which artemisinin is isolated has been in use in traditional Chinese medicine since probably about 300-200 BCE.
Many of these therapies, as well as those from other civilisations and cultures, despite being ignorant of the causes of infectious diseases, built on empirical observations, and thus might have been effective.
It is curious that skeletal remains from the Nubians of Sudan from ~400CE and of Roman Egypt show traces of the modern day antibiotic tetracycline; whether this was part of any herbal medication or was an incidental component of these people’s diet is anybody’s guess. At the end of the day, many antibiotics we have today are ancient, natural products, which as we will see later in the article contributes to making antibiotic resistance inevitable.
Vaccination against infectious diseases has a long history, and its afore-mentioned application in India 1,000 years ago seems to have had a relationship with the acknowledgment of a germ theory of disease. Vaccinations were also performed in China in the 14th century and in the Arab world in the 12th century. The practice was formalised in Europe by Edward Jenner towards the end of the 18th century. Even today however, vaccinations against bacterial infections have been rarely successful – a cursory glance at the immunisation schedules of our children will immediately point to a preponderance of vaccines against viral rather than bacterial diseases. To clarify, vaccines, unlike the antibiotics that were to revolutionise medicine later, do not treat an infection; instead they prime the immune system to provide protection against an infection.
The antibiotic era
The greatest success story of medicine in treating infectious diseases is the antibiotic revolution, initiated by Paul Ehlrich’s introduction of the “magic bullet” Salvarsan, a toxic arsenic-based agent, to counter syphilis in 1910. Not too long after, the first sulfonamide antibiotics were introduced by Bayer. The turning point of course was the discovery – by Alexander Fleming – and the mass production – by Howard Florey – of penicillin, which played a major role in curing infections during and after the Second World war. Penicillin is a natural compound produced by a type of fungus, referred to as a mold. It is notable that among ancient people, eating certain molds was a practice for treating some infections.
Penicillin is an antibiotic that acts by not allowing the bacterial cell to produce its own cell surface, called the cell wall. Bacteria are single cells and nearly everything they contain, and all that makes them a form of life are contained within a fragile detergent-like membrane, which in turn is protected by a hard cell wall, made of tightly interlinked chains of sugars and molecules called amino acids. If this protective cell wall can no longer be made, the fragile membrane gets exposed, and its rapid collapse will essentially annihilate the bacterium. Our cells do not have cell walls, and for us having just the membrane is more than sufficient. This means that penicillin cannot do much wrong to our own cells, making it a safe drug that specifically kills bacteria and leaving us unaffected. Of course, penicillin overdose causes liver toxicity and so on, but that is a different story altogether.
Bacteria have many other Achilles’ heels, besides the cell wall: these are biochemical functions essential for their survival, but evolved in such a way that the molecules responsible for these functions are very different from their human counterparts. This means that that drugs can be designed to specifically target these bacterial properties, leaving human biochemicals alone. For example, several antibiotic types such as the tetracyclines, aminoglycosides and macrolides inhibit the protein synthesising machinery of bacteria, but not of human cells.
Many antibiotics were made that controlled infections across the world and increased life expectancies significantly. All looked hunky-dory. Laden with irrepressible excitement, we flooded ourselves and our environment with antibiotics: taking antibiotics for every little sniffle, for the generic amoxicillin antibiotic in its yellow wrapping, and generously doled out by our pharmacies without a doctor’s prescription, cost next to nothing; using antibiotics in animal husbandry and poultry as growth-promoting agents and for prevention of infections; industrial dumping of large volumes of these molecules into rivers and waterways; in laboratories during for example genetic engineering experiments. In particular, the use of antibiotics in poultry and animal husbandry represents a major shift in antibiotic usage from treating to preventing bacterial infections, which has resulted in massive overuse of these drugs.
With great confidence and supposed vision, we decided that infectious diseases were a done deal, and research funding for these areas were curtailed in the US. After all what was the point of studying things that were on their way out of this world. Unfortunately, we did not factor in evolution.
Aswin Sai Narain Seshasayee runs a laboratory researching bacterial biology at the National Centre for Biological Sciences, Bengaluru. Beyond science, his interests are in classical art music and history.