Bacteria, bacteriophages and resistance - an evolutionary arms race

When I was a student at the University of Texas School of Public Health in the late 1970's, infectious diseases were a quaint, passé concern.  Smallpox had just been eliminated, we'd gotten tuberculosis under control, antibiotics could treat all the important infectious diseases of recent decades, as well as many unimportant ones, and we were moving on to addressing the diseases that had taken over as the leading causes of death, chronic diseases of middle and old age -- cancers, heart disease, stroke, and so forth. The Department of Epidemiology only had one rather ancient and bedraggled TB specialist still holding on, while Biostatistics was thrumming with hot new faculty.

And then HIV/AIDS happened, TB came back with a vengeance, drug and multi-drug resistant to boot, and drug resistant malaria started to spread.  Bacterial infections that we'd thought were easily controlled began to resist treatment, and public health workers began to worry that perhaps the future wasn't going to be all about controlling chronic diseases after all.  Now we've got MRSA, C dificile, gonorrhea, several classes of streptococcus, gram-negative bacilli, malaria, TB, and many other drug resistant bugs that used to be treatable and now are not.

We've passed peak antimicrobial and are on a fast slide to the bad old days when a simple infection was often lethal.  Much ink has been spilled, many keys have been tapped documenting the coming return to the pre-antibiotic era because our drugs no longer kill microbes.  The overuse of antibiotics in medicine and the widespread use of antibiotics in the food chain, in both agriculture and aquaculture, are the essential causes, but even used sparingly, resistance is inevitable because, well, because evolution.

It's been known since the advent of antibiotics in the 1940's that resistance was a potential problem, but we've not done nearly enough to prepare.  And, pharmaceuticals are no longer investing in research into new antibiotics in large part because their effectiveness is so short-lived, and thus the likelihood of recouping the cost of product development and going on to make a profit, in the time of wonder drugs like Viagra, which are goldmines worth investing in, is low.  Is there hope, or are we destined to go back to the days when simple infections and easy surgery were life threatening?

In a feature article in American Scientist last month, "How to Fight Back Against Antibiotic Resistance", Gautam Dantas and Morten O. A. Sommer write that the only hope is for scientists to figure out the molecular pathways that make resistance inevitable.  Probably they would say that, given that's what they do, but is that right?

Attention is being paid to a suite of genes called the 'resistome' (yep, yet another omics term), those genes responsible for, as the authors put it, turning a susceptible pathogen into a superbug.  Even so, understanding how bacteria resist death by the chemicals we throw at them is like generals fighting the last war.  As Dantas and Sommer put it, "the pool of resistance genes, and the mechanisms of resisting antibiotics, available to bacteria are effectively limitless."  Any new strategy we come up with, they'll come up with a way to resist.

How Phages Work

All known bacteria are thwarted by phages, which are extremely specific and only attack the strain of bacteria they evolved to inhabit and kill (mammalian and plant cells lack the receptors required for phage infection, so phages are harmless against them). Phages first attach to and puncture the bacterial membrane. Phage DNA is injected into the host cell. The host cell’s DNA transcription is suppressed, and phage-specific proteins are synthesized instead. New phages are assembled, the host cell membrane is disrupted, and large numbers of new phages are released from the host bacterium, which dies.22

Phages first attach to and puncture the bacterial membrane. Phage DNA is injected into the host cell.
© Medi-Mation Ltd/Science Source

The host cell’s DNA transcription is suppressed, and phage-specific proteins are synthesized instead.
© Medi-Mation Ltd/Science Source

New phages are assembled, the host cell membrane is disrupted, and large numbers of new phages are released from the host bacterium, which dies.
© Medi-Mation Ltd/Science Source

An estimated 1030–1032 phages exist in the biosphere,22 and an estimated 1023phage infections occur per second.24 Every 48 hours, phages destroy about half the bacteria in the world,25,26 a dynamic process that occurs in all ecosystems.14,24

Phages have infected bacteria for billions of years, and just as bacteria mutate to resist drugs, they also mutate to render phages ineffective. However, new phages continually evolve against the mutated bacteria.27 “It’s an evolutionary arms race,” says Daniel Nelson of the University of Maryland’s Institute for Bioscience and Biotechnology Research. Because phages cannot reproduce on their own, they must infect bacteria, which, in turn, spend massive amounts of energy trying to avoid death by phage.

However, phages are not totally bad and even offer bacteria a fitness advantage by transferring genes for antibiotic resistance and toxins to bacteria. To acquire desirable traits while avoiding death, bacteria use restriction modification systems to cut out deleterious phage DNA and keep beneficial phage DNA.27 “Nonetheless, phages adapt and evolve more rapidly than bacteria, so the cat-and-mouse game continues as both sides try to out-evolve each other,” says Nelson.

From Dantas and Sommer

A short essay in the New York Times last week by Matti Jalasvuori, in a Room for Debate discussion of antibiotic resistance, describes what some are seeing as a new old strategy, corralling bacteriophages, viruses, to target specific bacteria, which they do naturally, and kill them for us.  Phages were successfully used to treat infection in Russia in the pre-antibiotic era, but pretty much dropped with the development of penicillin.  They've caught people's interest again.

Jalasvuori writes,

Phages are natural antibacterial entities that continuously struggle for existence among diverse bacterial systems. They are as old as life itself, indicating that they have been successfully exploiting bacteria for billions of years already. Unlike chemical antibiotics, viruses evolve and therefore bacteria are unable to become resistant to all of their viruses. 

Some viruses have evolved to specialize on infecting bacteria that host hopping genetic elements. These viral agents can be directed to attack resistant bacteria for which alternative means of control have failed. Moreover, prolonged exposure to these viruses can cause bacteria to become treatable again with conventional antibiotics. This is because bacteria benefit by dropping the genetic element and thus becoming resistant to viral infection: evolution is acting in our favor.

Yes, bacteria can quickly develop defenses against phages by the usual evolutionary processes of mutation and natural selection, but the idea is that therapeutic use would involve cocktails of phages and a bacterium would be unlikely to become resistant to all of them.  This is the same evolution-based idea that motivates multiple drug attacks on cancer cells, TB, and so on.  The strategy will work for a while but everyone knows that even then, resistant they will be become, which is one reason that some people are interested in harnessing the mechanism by which phage kill bacteria.

Lysins, the enzyme that phages produce that make bacteria explode, are being isolated and explored as an alternative.  Like phages themselves, lysins would be bacteria specific.  It is thought to be very unlikely that bacteria can develop resistance to lysin because they've co-evolved, and, according to Fenton et al. in 2010, "...lysins evolved to target specific molecules in the host peptidoglycan that are essential for bacterial viability."

Maybe, and indeed we have what is known as the 'innate' immune system (contrasted with our other, 'adaptive' antibody-based immune system that changes all the time to attack whatever we may be infected with).  In a nutshell, the innate system attacks general properties of bacteria and other pathogens, rather than species-specific ones, working on fundamental aspects of the outer covering of the pathogens' cells that is more generic and less subject to mutational variation.   So we'll see how approaches such as targeting with lysins fare.

Another question is whether phages will mutate to become harmful to eukaryotic cells -- us -- or whether they could spread resistance genes via horizontal transfer, or whether there will be unintended, unforeseen consequences are also important concerns.  And, they do trigger the immune response so each one could be used in any individual only once.

Is there a permanent solution to the antimicrobial resistance crisis?  No, because evolution.  But phages may be a possible short-term strategy, and they should be tried.