Antibiotic Resistance is Inevitable But Not Insurmountable

Resistance is here to stay but it needn't be apocalyptic. The challenge for the human mind is to keep pace with it and keep a continuing stream of new antibiotics with novel properties flowing.

This article is the second of a two-part essay on antibiotic resistance. The first part is here.

Even before penicillin was commercially introduced, resistance to it was described! All organisms evolve at some rate, and bacteria with their large population sizes and fast reproduction times can generate, by random chance, a humongous number of genetic variants, some of which might carry the property of resistance to antibiotics. A bacterium does not necessarily have to mutate its own chromosome to become resistant, even though multi-drug resistant Mycobacterum tuberculosis evolved in this manner; bacteria can share determinants of antibiotic resistance amongst each other by a phenomenon called horizontal gene transfer.

Resistance is generally conferred by proteins that modify the antibiotic and convert them into non-toxic forms; proteins that throw the antibiotic out of the cell; alterations that block access of the antibiotic to its target locations inside the cell; modifications to the target of the antibiotic such that the target is no longer affected by the antibiotic.

In an environment that is saturated with antibiotics, those variants which can survive the drug onslaught outcompete their relatives and take over the population. Eventually, we end up finding that a large number of bacteria that we have to deal with are impervious to the weapons we use to tackle them. A bit like the fast-multiplying rakshasa on whom a helpless minor deva throws ineffective arrows.

It is easy to see how antibiotic overuse can result in a more or less permanent selection of antibiotic resistant bacteria: the bacteria rarely see an antibiotic-free environment and therefore the less likely that there will be some that are sensitive to the antibiotic. Resistance to drugs is not limited to bacteria. Variants of HIV are resistant to the protease inhibitors used in therapy; we know of chloroquine-resistant malarial parasites; and cancer cells do become recalcitrant to chemotherapy.

The problem is compounded by the fact that most antibiotics are “broad-spectrum”, in that they are not specific to a small variety of bacteria but in fact target vast swathes of their range. There are good reasons for having broad spectrum antibiotics: it is not always practical for a doctor to specifically diagnose the bacterial variety causing an infection and in these situations a generalist antibiotic works. There are commercial reasons for the goodness of broad-spectrum drugs as well. On the flip side, having broad-spectrum drugs means that evolution of resistance need not necessarily arise in the specific bacterium that needs to be targeted but could evolve in any of the zillion other harmless bacterial species that the antibiotic affects, and then eventually find its way to a bacterium of our concern by horizontal gene transfer.

Resistance is futile inevitable

Let us take the case of cell wall-targeting antibiotics and track the emergence of resistance. The first source of resistance to penicillin was the presence of certain enzymes in target bacteria. These enzymes, called beta-lactamases, break down penicillin into harmless compounds. Bacteria may evolve a lot faster than humans but humans with their big brains do not have to evolve to come up with new ideas. So the scientists hit back and came up with penicillin variants that can do the originally intended function of penicillin, but be impervious to the action of the beta-lactamases. Excellent! The problem is that bacteria evolve and do it rapidly. The new strategy that the bacteria came up with was to find a mutation in the protein that penicillin targets, thus making the protein insensitive to penicillin and its variants. Take that and that – a one-two punch.

The bacteria even found other variants of beta-lactamases that could breakdown the wide-range of penicillin variants that humans could come up with. There are probably only two types of antibiotics today that can target what are called extended spectrum beta-lactamase producing E. coli, which cause infections in the urinary tract. There is hardly any pathogenic bacterium (with the possible exception of Treponema pallidum, the thing that causes syphilis) that is not resistant to the original penicillin today.

British scientists working with the company Beecham discovered that we could inhibit beta-lactamases themselves using something called clavulanic acid – the famous Augmentin (or Clavam) that doctors often give as a first-line antibiotic today is a combination of amoxicillin (a penicillin variant) and clavulanic acid. But well, all that bacteria have to do was find beta-lactamase variants that are resistant to clavulanic acid, and they did just that. And the story is endless. Even with last-resort antibiotics like vancomycin, whose structure and activity in affecting cell wall assembly are so complex that bacteria had to evolve entirely new systems of proteins (not one protein) to develop resistance, bacteria have found ways out.

We now realise that resistance is inevitable. As Julian and Dorothy Davies say in their article ‘Origins and Evolution of Antibiotic Resistance’, “if resistance is biochemically possible, it will occur”. Of course, it is not always clear that resistance is biochemically possible, at least within a few decades or even centuries. But as we will see below, there are good reasons why it is not just biochemically possible, but has been primed to be possible for millions of years!

The beginning was a few million of years ago

Most antibiotics are variants of natural compounds, and many produced by varieties of bacteria and fungi. Now you see, there lies a problem. Someone who throws out a noxious fume to destroy much of life around him, will try to make sure he does not succumb to the fume and will wear a mask, unless of course he is being suicidal. Similarly, if a bacterium had to produce antibiotics to keep its competition in check, it itself had to be resistant to the antibiotics. That means antibiotic production in nature, which has been happening for millions of years, should be associated with resistance. In fact, the afore-mentioned last resort vancomycin is produced in nature by a bacterium, which carries the entire set of proteins it needs to ensure that vancomycin production is not suicidal.

And bacteria targeted for killing by these antibiotic producing bacteria and fungi themselves would have evolved resistance, completely independent of human excesses. The arms race between microbial killers and their targets is fascinating. In fact, clavulanic acid seems to be an old strategy used by a microorganism to counter resistance among its competitors to the penicillin-like antibiotics it produces. It is not surprising that we now find antibiotic resistance in random bacteria isolated from natural environments; we have even found bacteria that eat antibiotics for breakfast, lunch and dinner, like an Indian movie hero would threaten to do to the villain and his minions.

It’s been argued that resistance involves a tradeoff – a bacterium that is resistant to an antibiotic might lose out to a sensitive competitor if the antibiotic is removed from the environment, resulting in a cost of antibiotic resistance. Thus, would it be possible to “reverse resistance”? Probably not. Why? Even though high levels of antibiotics in the environment are definitely of anthropogenic origins, low levels of antibiotics should have always been there in the soils, in the waters, thanks to their production by bacteria themselves. Even with humans dumping antibiotics everywhere, the concentration of these molecules in the environment is probably less than what would be needed to be lethal to a bacterial population. As has been shown by Diarmaid Hughes and Dan Andersson, very low levels of antibiotics, even if insufficient to wipe out a population of bacteria, can still select for variants that are resistant to the antibiotic.

As predicted by Hughes and Andersson some years ago, and more recently shown experimentally by Aalap Mogre, a PhD student in my laboratory, bacteria growing in low concentrations of antibiotics can quickly find low-cost mechanisms of resistance. In other words, evolving resistance under low concentrations of antibiotic rapidly remove the above-mentioned tradeoff from the equation, cruelly shutting out the dim ray of hope that might have otherwise emerged. Low levels of antibiotics are likely within the body of the human who fails to adhere to the antibiotic dose regimen prescribed by her physician; so do think twice about buying an antibiotic from a pharmacy without a prescription, and do think twice before you decide to deviate from an antibiotic regime prescribed by your doctor.

A final problem with antibiotic resistance is that most proteins that confer resistance to an antibiotic are very closely related to ancient proteins that perform core functions in the bacterial cell. For example, beta-lactamases are related to the enzymes that help assemble the cell wall in normal bacteria. Thus, a bacterium does not necessarily have to create an entirely “new” resistance determinant; it can find something that it already has, make a few changes to it and get the job done. End of story!

A new beginning

With antibiotic resistance being recognised as a serious problem, there has been significant research activity in this field. We are trying to discover novel ways and means by which bacteria go about doing their daily routine; how antibiotics affect these processes; how the bacteria counter antibiotics. For example, the laboratory of J.J. Collins has argued that many antibiotics, despite having widely different direct targets in the bacterial cell, commonly affect certain other physiologies of the bacterium, and a level of resistance could evolve in the bacterium by altering these physiologies.

Novel antibiotic treatment strategies are being developed by academic laboratories. The laboratory of Roy Kishony has systematically shown that certain combination regimens of different antibiotics – not all given together, but in some alternating or cycling fashion – could delay resistance. Drugs that target the ability of the bacterium to cause disease, but not quite kill the bug, is an idea that has been floated and being tested. The problem with this approach of course will be if the disease process itself is necessary for survival; then selection would result in resistance. Treating bacteria with viruses that feast on them can be traced back to Félix d’Herelle in the 1910s, and remains an experimental therapy in certain Eastern European countries. May be the time is ripe to open our eyes to these approaches.

My colleague Varadharajan Sundaramurthy has worked on mechanisms of countering Mycobacterium tuberculosis not by directly hitting the bacterium but by resetting host physiologies that are upset by the bacterium. This may sound at one level like the ideas of our ancients but we must note that this operates at a significantly higher level of sophistication at the molecular level. This can be considered as a class of experimental therapies that can be based on the idea that virulence evolved as a result of immune system over-response, and targeting the latter would be a strategy to counter the former.

Finally, a group of laboratories, including biologists and researchers in the humanities, have reconstructed an anti-microbial recipe described in the Anglo-Saxon Leechbook of Bald, and after a systematic investigation showed that it could kill multi-drug-resistant MRSA bacteria. While on this subject, it is also prudent to remember the antimalarial artemisinin. With regard to reviving herbal remedies, one needs to consider the logistical problems of scaling up production to levels that are socially relevant.

At the end of the day, resistance is here to stay. But it need not be apocalyptic. The challenge for the human mind is to keep pace with it and keep a continuing stream of new antibiotics with novel properties flowing, and also finding ways by which resistance can be slowed down, including tight regulatory controls for ensuring their prudent use especially in countries like our own. It is doable, as long as we do not let our guard down.

The author thanks Dr. Savitha Kamalesh at the St. John’s hospital, Bangalore, and Dr. Varadharajan Sundaramurthy at the National Centre for Biological Sciences, Bangalore, for their critical comments on this article.

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.