The recent wars in the Middle East and the biological phenomenon of multi-drug resistance (MDR) look like two unrelated subjects. One is a large topic in international affairs while the other is a general problem in human health, seemingly unconnected to politics. In this piece, I will explain what the connection is and why it is important.
It would be useful first, however, to first review some history, that of antibiotics. Antibiotics can be defined as substances made by fungi that are deadly to bacteria but not harmful to humans.
Their discovery in the third decade of the 20th century and the subsequent mass development of antibiotics for medicinal treatments was one of the great advances in medicine in the 20th century and has undoubtedly saved tens of millions of lives. The success of antibiotics lies in their preferential killing of bacterial cells while sparing human cells. The basis of this difference lies in the different structures and biochemistry of bacterial vs animal cells, which in turn reflects the unique bacterial features that can be selectively targeted by drugs.
Before true antibiotics, there had been several chemicals discovered, from the late 19th century onwards, that preferentially killed infectious bacteria; before them, there had been no effective therapies for such diseases. The sulfonamides, first discovered by the chemist Paul Ehrlich, were in the forefront of such therapies. However, they and the others that came along in this period, often had side effects in humans and their doses had to be particularly carefully calibrated to avoid those side effects.
The first antibiotic discovered was produced by a fungus that was often found as a mold on older pieces of bread, Penicillium notatum, and its effects were first noted and described by a Scottish physician, Dr Alexander Fleming in 1928. It was truly a serendipitous discovery, involving accidental contamination by the fungus of some agar plates on which Fleming had been cultivating bacteria. Normally, in labs when such contamination occurs, one simply discards the plates and starts over again, trying to avoid contamination. But Fleming thought about what he was seeing. There were clear zones around the fungus, clear of bacteria that is, and Fleming realized that the fungus must be producing something that was killing the bacterial cells. He purified the active substance and found that it did have powerful antimicrobial activity, publishing his results in 1929.1
The next steps were taken in the following decade but the net result was that the active compound, penicillin, proved to be a major help in saving Allied soldiers lives toward the end of WWII. Penicillin was a real asset for the Allies and did so by saving human lives, not taking them.
The importance of agents that could discriminate between bacterial and human cells, killing the latter, was obvious and apparent. Penicillin’s success set off a major race to find and purify and test other such compounds, obtained from fungi, beginning in 1945. Indeed, the period from 1945 to the early 1970s is rightly considered the Golden Age of antibiotics, as many new ones were discovered, and developed for commercial use, often proving brilliantly successful in curbing bacterial infectious disease. Modern medicine truly came of age in the 20th century and the discovery and use of antibiotics was one of the two major elements in that success.2
Yet, the delineation of a period as a Golden Age implies that what followed was, in some degree or some way, a decline from that pinnacle of success. By definition, Golden Ages come to an end. To understand what happened in this particular case, it helps to consider why so many fungi produce antibiotics in the first place. Clearly, they are not doing so for the benefit of humans. There must be some benefit for the fungi themselves and there probably had been since the early days of fungi as organisms on planet Earth, estimated to be at least 700-800 million years ago. Fungi that live on or in the soil share their environment with bacteria and compete with them for nutrients and, at times, undoubtedly, for living space. Producing those compounds, which we now term antibiotics, is a large part of how they carry out this competition. The bacteria so killed are not just eliminated as competitor cells but almost certainly supply nutrients for the fungi.
It is in the nature of competition, however, that whichever party seems to be losing the fight will try to develop ways to combat the weapons of the successful group.3 And, in this case, bacteria have indeed fought back. They have done so by developing counter-measures, modes of resistance, to the antibiotics. Such responses can be seen as a biological “arms race”. How this works out in the natural environment, quantitatively and over time, is still little known since to explore that would require experimental intervention that would itself change the conditions dramatically. How this plays out on the battleground of the human body, however, has been clarified in great detail by roughly a half-century of intensive research.
The essence of the bacterial response to antibiotic presence is to produce genetic changes that confer resistance to the antibiotics. Those changes allow the bacteria to survive and reproduce in the presence of the antibiotics and thereby escape the latter’s lethal effects. Rare mutants that are resistant to particular antibiotics were observed from the first tests on any potential new antibiotic. They would show up as isolated colonies on agar plates that had had the target bacteria spread on them along with the presumed antibiotic. Most of those test cells would die, if the new compound were effective, but rare cells would harbor mutations that would allow those cells to survive, reproduced by repeated cell divisions and yield a colony.
Hence, the phenomenon of drug resistance was known and appreciated from the early days of the antibiotic revolution. Furthermore, its potential importance as an escape route for infectious bacteria exposed to an antibiotic was appreciated from the beginning. Killing of bacterial cells by an antibiotic was, in effect, a strong evolutionary “pressure” for selection of those cells. Furthermore, the more that antibiotics were used in humans, the more resistant cells could be expected to arise. Potentially, this was a threat to the long-term efficacy of antibiotics: the antibiotic-sensitive populations of infectious bacteria could be replaced, over time, by resistant versions, which would not be touched by these drugs. This warning was issued at virtually the start of the era of antibiotics, in 1945, by none other than Alexander Fleming, the discoverer of penicillin.
And so it came to pass, that over a period of roughly 30 years, antibiotics went from being the supreme weapons against infectious bacteria to, increasingly less-and-less effective ones. At first, however, it did not seem to be a problem because of the rate at which new antibiotics were coming on to the market. As doctors were finding increasing numbers of patients who were not responding to a particular antibiotic, they would switch to one of the newer antibiotics. The problem, however, was growing as more and more antibiotics were being prescribed for patients or applied in other ways. One of the most important of the latter was the use of antibiotics as a preventive measure of disease in animals in agriculture, such as chickens, cows and sheep.
Furthermore, since many antibiotic molecules are not degraded in people or animals, they tend to be excreted, in feces or urine, hence released into the environment. The more administered doses of antibiotics there were, the more they spread into the environment, particularly the water ways (streams and rivers) which would spread them further. And the more that bacteria were exposed to them, the more resistant bacteria there would be. This was all perfectly predictable and indeed had been predicted, as noted above. Yet, the pressures for antibiotic use were so strong, both in medicine and agriculture, and the limitations on their use so weak, that the trend continued. Indeed, the problem of antibiotic-resistance became measurably worse. This involved two developments.
First, the pace of discovery of new antibiotics had sharply slowed by the early 1970s. At the same time, the problem of resistance grew, both in terms of the numbers of patients who were not responding to antibiotics and in the numbers of antibiotic drugs that were losing their efficacy. The result was that the prior strategy of going to a new antibiotic when resistance levels to the previous drugs had become high was no longer feasible.
Second, a brand new phenomenon began to show itself: multi-drug resistance, abbreviated MDR, in infectious bacteria. This was wholly unexpected by the medical profession as a whole and, I believe, by the great majority of evolutionary biologists, who would have sounded the warning if they had seen this coming. (If any readers know of prescient warnings of MDR, please let me know in the comments.) In conventional genetics, mutation rates are low, on the order of 1 in 108 cells/gene/cell division. Correspondingly, newly-arising resistant mutants should be comparatively rare, as indeed they seemed to be in the first observations in the 1950s. Hence, the chances of getting a new mutant that was resistant to two antibiotics should be vanishing small, on the order of (10-8) x (10-8) or 10-16. What increasing numbers of doctors were discovering was that some of their patients were resistant to two or three or more antibiotics. This was not a fluke of some sort but a trend, in terms of the increasing numbers of patients harboring such antibiotic-resistant infections.
Furthermore, hospitals were increasingly the source of these MDR infectious bacteria. This made perfect sense in that hospitals were increasingly the centers at which antibiotics were administered, to control and reduce chances of infection, hence the places where the evolutionary selection pressures for antibiotic-resistance would be the strongest. Yet, this was, simultaneously, a horrible irony: hospitals are the places you go, as a last resort, to be treated and, one hopes, cured of serious health problems. Now, however, they were becoming the epicenters of spread of MDR bacteria.
To deal with the MDR phenomenon, it had first to be understood. Initially it was a mystery but the answer was soon forthcoming. Bacteria, like eukaryotic cells, have DNA as their hereditary material but unlike those more complex cells, they typically have only one chromosome and instead of it being linear, it is circular. Yet, many have smaller, accessory DNA elements in addition, which are also passed on to each “daughter cell”, the two products of each cell division. Those small circular DNA elements are termed “plasmids”. It turned out that the MDR phenomenon was due to plasmids that carried two or more (sometimes many more) resistance genes to (different) antibiotics. These small sets of resistance genes were initially tied together by the process of genetic recombination, to form new plasmids. These can then can be transmitted as units in each cell division. When descendant cells carrying such a plasmid encounter one or more of the antibiotics for which they carry resistance genes, they are strongly selected and passed on to their descendant cells, who acquire the encoded drug-resistances.4
By the late 1980s and early 1990s, antibiotic resistance had become a major problem for medicine and a magnified one relative to that which had been forecast by a few in the 1940s and 1950s. I remember attending a high-level conference on this topic in London in the early 1990s. By then, the MDR genie was well and truly out of the bottle.
I stress: the basic problem had been foreseen. While the special twist of the MDR phenomenon had not been, the general problem of antibiotic-resistance had been predicted, yet the use of these drugs had become promiscuous and the problem had ballooned. In this respect, it is rather like the phenomenon of global warning and climate change: foreseen in plenty of time but pushed off into the future for later generations to deal with. In 2019, the number of people who had died from infection by MDR bacteria was estimated at 700, 000. By 2050, or 25 years from now, the predicted estimate is 20 million deaths from this cause and the monetary cost on the order of $2.9 trillion. These figures are on the order of the Covid-19 pandemic of 2020-23, a health catastrophe. Of course, thought is being given to how the potential MDR disaster can be avoided or at least reduced in scope but there are no sure-fire solutions at present.
Let us return to our opening paragraph: how does the subject of MDR connect to the wars in the Middle East of the past few decades? It does so in several ways. My comments here are based on an article in the international edition of The New York Times that appeared in the 7th-8th December, 2024 edition.5 Its short title gives the conclusion, “Warfare is breeding fearsome superbugs”, and is based on observations from four major war zones – Iraq, Syria, Lebanon and Gaza – and interviews with the medical people involved.
The first route through which war promotes MDR bacteria is the most direct. War does not just kill people, its worst horror, but it causes many more to be wounded, both civilians and soldiers. If they are not attended to quickly, the wounds become infected and fester further. With MDR bacteria already loose in the world, massive new numbers of wounded people become potentially massive breeding grounds for MDR bacteria. Second (and this is not stressed nearly enough in my opinion), wars greatly increase the stress levels of all those in the vicinity of military actions, even if they are not directly hit. Physiological stress weakens the immune system and makes people more susceptible to bacterial infection. If, in addition, there is insufficient food and resulting malnutrition, these effects are magnified. Viral infections go up too, of course. (I suspect it is not a coincidence that the biggest and most lethal viral epidemic in history, the “Spanish ‘flu” of 1918, took place in the last year of WWI.)
The third way in which war promotes the spread of MDR bacteria is indirect. Antibiotics are often available in or near war zones but frequently in insufficient quantities for the numbers of wounded and the doses required. The understandable response of health professionals, even though they know that this is a mistake, is to give reduced doses of the drugs to spread out the help supplied. This partial dosing may initially reduce infections and their severity but it gives the opportunity for slightly resistant bacteria to multiply and to become more resistant. This has almost certainly been happening to Palestinian civilians in the war in Gaza, due to the deliberate great reduction of medical supplies to the civilian population by the occupying military forces.
The fourth mode is the subtlest: the exposure to metal particles from munitions that cause wounds. This has been most carefully documented for a bacterial group named Acinetobacter. These organisms respond by inducing a biological “pump” that gets rid of the metal atoms. These molecular pumps, however, also more efficiently expel antibiotics that have entered the cells. This too promotes both immediate and long-term multi-drug resistance. The basis for the latter is that when an induced condition promotes survival, however it does so, this often favors mutations that create the same effect.
Altogether, the recent wars in the Middle East are probably going to turn out to be major breeding grounds for MDR bacteria. Yet, in our thoroughly globalized world, these bacteria are bound to migrate to other parts of the world just as MDR bacteria from hospitals already do.
To return to the opening thought in this piece: one typically regards matters of world politics as distinct from matters of science. In fact, the relationships between human affairs, impacted by politics, and matters of biology are often intimate and significant. Indeed, elucidating those connections is the aim of this newsletter. The links between war and antibiotics, from WWII and the triumph of antibiotic therapy by penicillin, and the current wars, where antibiotics have helped breed super-bugs that are spreading misery and death, are an excellent example of how closely linked these worlds are.
A similar observation on a different species of Penicillium had been made by Paul Ehrlich, in 1871 (!) where he had shown that it produced a specific bacterial killing agent. For reasons that are unclear to me, he apparently did not try to take this work further as a therapy.
The other big 20th century area of major medical success was in vaccines, especially against viruses; think of the success of eliminating smallpox and the huge reduction in polio cases. Antibiotics are useless against viral infections because viruses use the cellular machinery of their host cells (eukaryotic cells) and so many of the drugs that interfere with virus multiplication equivalently harm the host cells.
A parallel situation involves plants and insects. Plants, which cannot move away from their sites, would seem to be sitting ducks for the insects that eat them but the plants fight back with compounds that kill insects. Some plant species have many hundreds of such compounds, a truly impressive evolutionary response.
A good review of the history and biology of this phenomenon is that of Uddin, T.M. et al. (2021). Antibiotic resistance in microbes: history, mechanisms, therapeutic strategies and future prospects. J. Infect. & Pub. Health 14: 1750-1766.
See Francesca Mari, “Warfare is breeding fearsome superbugs”, The New York Times, Intl. Edition, 7-8 December, 2024, p. 1.
Adam: Friggin’ brilliant piece!