Turned up to eleven: Fair and Balanced

Thursday, July 25, 2002

When bacteria attack (each other)
Charles Murtaugh is riffing on antibiotic resistance, and explaining very well how it is a strong reminder of the power of natural selection. Since this is the field I work in, and I spent some time studying antibiotic resistance in particular, I feel it is my right, nay, my responsibility, to add my 2 cents.

My friends and loyal readers, you have been misled by the slogan "better living through chemistry", in particular in the realm of microbicidal drugs and antibiotics. A better slogan would be "better living through emulating microbes". The reason for this is, as mighty and powerful as the pharmaceutical industry is (and I mean that in the most positive sense), the source of the vast majority of antimicrobial drugs and chemotherapies...bacteria themselves. The evolutionary explanation for this is that bacteria have been fighting amongst themselves, like petulant siblings, for millions, if not billions, of years (probably billions, in fact). The man who led the charge in discovering this, of course, is the famous Alexander Fleming, whose dirty lab and old, stale cultures were the incubator for one of the great discoveries of the 20th century (a beacon of hope to the disorganized and messy among us!). Further research has discovered that other bacteria, most notably of the genus Streptomyces, are veritable pharmaceutical plants, pumping out chemicals by the dozens, including a number of the basic antibiotics in use now. The list of antibiotics currently available, for human, animal, and research use, is huge. What is generally not understood is that, with the exception of one class of (not very effective) drugs, sulfonamides, all of them are either natural products, or derivatives of natural products. That is to say, human beings have very rarely been able to synthesize de novo a drug that selectively inhibits the growth of hostile microbes without harming the patient. This is, of course, a daunting task (ask Derek Lowe if you don't believe me), and it is no great surprise that chemists have a hard time equaling or surpassing billions of years of natural selection.

Something that was underappreciated at the time of penicillin's discovery, and remains misunderstood or ignored outside the realm of microbiology, however, is the problem of antibiotic resistance. A common misconception is that people become resistant to antibiotics ("I've taken that drug so many times, I have built up a resistance to it"). There is, actually, a grain of truth in this thinking. The illnesses people get are often caused not just by microbes taken in from the environment, but also by microbes that are always in our bodies. People who get chronic sinus and upper respiratory infections, for example, are probably having latent microbes in those passages reactivating and growing over time, and taking the same drug over and over again can breed resistance in those sites. Opportunistic infections by microbes that are always present on or in us, but only attack when some other injury has wounded us, can also become resistant to antibiotics given for other, previous illnesses. Finally, not taking the full course of an antibiotic can have the effect of leaving a small, temporarily non-infectious population of the offending microbe that is resistant to the dose of antibiotic given. Fundamentally, this is a war that is not winnable through the conventional pathway of natural products drug discovery. Why is that?

When bacteria fight, antibiotics are the weapons of choice. What many overlooked at first, and later discounted, is the notion that the attacking organism has to protect itself from the weapon. The bacterium making a "magic bullet" antibiotic has to also make itself some Kevlar. The reason is simple; chemicals don't know your name! The drug that the bacterium uses to kill its enemy is potentially just as dangerous to its source. Fortunately (or unfortunately, as we will see), natural selection has rid us of microbes that can't protect themselves, and thus bacteria have resistance mechanisms to every antibiotic they produce. This is vitally important to understand. If a drug is found in nature, then resistance to it is also found in nature. Now, here is the really interesting part; modifications to the drug in question only delay, and do not prevent, the rise of resistance. I will now bore you to tears with an example, from the history of a class of antibiotics, beta-lactams, the group of which penicillin is the parent, and the bacterium Staphylococcus aureus, which has done a remarkable job of rendering these drugs useless (against it, not everything).

Penicillin was first used clinically in the 1940's, and was tremendously successful. Contrary to what I said above, however, medicinal chemists were already modifying side groups on the molecule, looking for 1) greater efficacy, and 2) to avoid resistance. The first real success in this was methicillin, a derivative with a rather large side chain that made it less recognizable to the resistance mechanism that was already arising, beta-lactamases. Staphylococcus aureus, however, is a very clever bug, and it found a way to be resistant to methicillin, giving rise to a strain type referred to as Methicillin Resistant Staphylococcus Aureus (MRSA, sometimes also called Multiply Resistant Staph Aureus, for reasons to follow). Unfortunately, when a microbe became resistant to Methicillin, it simultaneously gained resistance to all other beta-lactam antibiotics! This was, and is, a huge problem, because beta-lactams are still the first line of defense against many infections, even though resistance to some of them is extremely widespread. The reason for this boils down to their target (called, prosaically, a Penicillin Binding Protein), which is an enzyme that builds the bacterial cell wall, or murein, also called peptidoglycan. This biochemical process is utterly absent in humans; nothing even closely related exists, making beta-lactams much less prone to side effects than other drugs, such as Ribosome inhibitors.

In any event, the methicillin resistance gene in Staphylococci is actually carried on a transposon, which is mobile element of DNA, that can be passed from bacterium to bacterium. Fortunately, it doesn't seem to be one that moves around a lot, at least not between species, so the problem of this particular type of beta-lactam resistance is relegated to Staph. Unfortunately, having this resistance mechanism seems to correlate very strongly with picking up other resistance mechanisms, most notably Multi-Drug Efflux Pumps, which can make Staph even more resistant to conventional antibiotics. The last resort in MRSA infections (and the closely related MRSE, methicillin resistant staph epidermidis, the most common cause of hospital catheter infections), has been vancomycin, which is a very powerful antibiotic, that also inhibits cell-wall synthesis, but by a different mechanism. So we are safe, right? Wrong!!

Another organism that commonly causes hospital infections is Enterococcus (most commonly Enterococcus faecium, an intestinal microbe). Now, the Enterococci are intrinsically resistant to many antibiotics, because they are "DNA scavengers", and "promiscuous", in the sense that they eagerly trade mobile elements such as the transposon mentioned above, as well as plasmids (sort of a mini-chromosome), and bacteriophage (viruses that infect bacteria). Vancomycin had to be used on these microbes, because it was the only effective drug in many cases. Not surprisingly, VRE (vancomycin resistant enterococci) quickly arose. A few years back, an investigator showed that if you mix MRSA and VRE together, you fairly quickly get a subpopulation of Staph that is resistant to all known antibiotics. Sure enough, a few years later, VISA (vancomycin intermediate S. aureus) and now full blown VRSA were found in hospital infections.

Are we doomed, then, to fight a continual losing battle? I have thought about this a lot, and I think for the time being, we are. Simply put, human ingenuity is no slouch, but billions of years of natural selection are a pretty formidable foe. Genomics has, and will continue, to give us new targets, and drug companies, finally roused to the danger of multiply resistant pathogens, will respond with new drugs, but if they are based on natural products, as seems likely, then resistance will not be far behind. Of course, many lives will be saved, and this is obviously a good thing, but I fear the dreaded "paradigm shift" is necessary if we ever hope to conquer infectious disease in any significant way. My next post will delve deeper into that last notion, including some cool vaccination ideas and bacteriophage based therapeutics.