January 1, 1970 (Vol. , No. )

Zachary N. N. Russ Bioengineering graduate student UC Berkeley

One of the more popular classical myths is that of Sisyphus, a trickster who humiliated the gods and escaped death. As punishment for his hubris, Sisyphus was condemned to an endless cycle of rolling a boulder up a hill, only to watch it roll back down again. Sisyphus’ ordeal is the widely invoked symbol of repetitive, frustrating tasks.

Sadly, one such task is the ongoing maintenance and development of our antibiotic repertoire. Instead of pushing a rock up a hill, we have:

  • Antibiotic discovered that preferentially targets some molecular element specific to the bacterial life cycle.
  • Antibiotic converted into a drug (through an increasingly expensive regulatory pathway).
  • Widespread deployment.
  • By its very nature, antibiotic confers a reproductive fitness advantage to resistant strains.
  • Virulent bacteria gain resistance through mutation or DNA exchange.
  • Resistance spreads.
  • New antibiotics are needed—repeat from start.

This process continues indefinitely—bacteria have biochemical processes distinct from those of normal human cells so there will always be potential targets for treatment; but you can’t kill all of the strain, and the survivors will reproduce.

We seem to be slipping behind, however. Large drugmakers are exiting the antibiotics market, and the number of antibiotics released each year has continued its steady drop. Meanwhile, new bacterial adaptions are being found around the world, and incidence of resistant infections are growing. Over 63,000 patients die in the U.S. because of resistant bacterial infections; a majority of staph infections are methicillin resistant (MRSA). The boulder is almost on top of us again.

Pushing Back

A large portion of public discourse is focused on policy (legislative, regulatory, and commercial) responses to the epidemic: control of overprescription, reworking incentives for hospitals and physicians, and regulation of usage in farm animals. These are all wonderful ideas if the political will could be found to implement them.

There’s another reason why policy options take precedence: New drugs are hard to make, and the process is not reliable. The most basic approach, making new molecules similar to the antibiotics we have, employs organic synthetic chemistry, and that is difficult. So is testing every natural compound under the sun for bacteriocidal activity.

In the molecular toolbox, two shortcuts have emerged: using adjuvants to inhibit bacterial-resistance mechanisms and using fragment design together with rounds of high-throughput selection. The adjuvant method has produced some successes such as Augmentin (clavulanate adjuvant and amoxicillin), while the high-throughput fragment method has produced some new adjuvants that have yet to make it to the market.

These methods may not be sufficient. To beat bacterial adaptation, we need faster drug development or slower evolution.

The solution to this life-or-death problem could come from life itself. Several classes of antibiotics, including polyketides and peptides, lend themselves to in vitro synthesis with an engineered enzyme. These enzymes have domains that are easily swapped, allowing rapid generation and screening of combinatorial libraries. The natural lipopeptide daptomycin has led to several promising candidates through this method.


It is also possible to re-tune the bacterial ecosystem in our favor. First, we can introduce predators. Vaccines, when available, can prove to be very succesful. The Hib (Haemophilus influenzae) vaccine reduced the number of cases by two orders of magnitude, and along with it, bacterial meningitis and pneumonia fell as well.

Phage therapy, the introduction of antibacterial viruses, has entered clinical trials with initial success. Phages can even be used in sutures and dressings and can be engineered to light up (using luciferase genes) when they have infected bacteria!

The other option is to modify the competition. Instead of trying to kill the offending bacteria, treat the human body as a natural habitat for bacteria, most of which are harmless. Since virulence factors are not as important to survival as, say, ribosomes, the selective pressure favoring any resistant bacteria will be much smaller.

One interesting target for inhibition is quorum sensing (QS), the bacterial communication necessary for coordinated attacks (as in cholera) or biofilm creation (like in chronic Pseudomonas infections). Several strong QS inhibitors have been found and demonstrated to work against biofilms and toxins, though, trials of one, azithromycin, were canceled due to funding problems.

Finally, it might also be possible to introduce harmless bacteria to crowd out the pathogenic ones, as was done in trials of an engineered nontooth-decaying S. mutans strain.

Bacteria will always find a way to surprise. In the azithromycin QS inhibitor trial, while the wild-type expressed less virulence, a population of freeloading QS-oblivious, less-virulent mutants also decreased. So while you might see some success with the “harmless competitor” approach, it could be negated by a QS treatment.

Unpredictable as the process might be, we must continue to develop new approaches to controlling microbial infections, at least to account for that which policy cannot. That boulder isn’t going to get any lighter.

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