Jan 09 2015

Antibiotic Resistance and New Antibiotics

Humans have a massive footprint on our ecosystem. Enough so that we have to think carefully about anything we do on a large scale, such as agriculture, industry, shipping (because of invasive species), and using drugs to fight bacterial infections.

The development of antibiotic resistance is a particular worry of mine, and one that I feel does not get proportional attention in the media. It is quite possible that in the future more people will die from antibiotic resistant bacteria than global warming, food shortages, or disrupted ecosystems (depending on how each of these things develop).

We are already seeing more deaths from drug-resistant bacteria, longer hospital stays, and greater costs. I have seen this change during my career. When I round in the hospital I now have to don protective garments before entering many patient rooms because they are infected or even just colonized with a resistant strain of bacteria.

There is no way around the fact that were are engaged in a war with the subset of bacterial species on this planet that are capable of infecting humans. We have been winning for a while, but the bacteria are now rallying.

Antibiotics either stop bacteria from reproducing (bacteriostatic) or kill them outright (bacteriocidal) by disrupting some aspect of their biology that is different than eukaryotic cells (the kind of cells that comprise multicellular organisms like people). The problem is evolution – random mutations can change the targets of the antibiotics in order to make the bacteria resistant. During a single infection bacteria may reproduce billions of times, offering many opportunities for such mutations. The antibiotic then provides the selective pressure, allowing the resistant bacteria to survive, and perhaps even fine tune their resistance.

Making matters worse, bacteria can easily swap genetic information through plasmids, little circles of DNA, and so one resistant strain can share their resistance with others. In fact plasmids that contain the ability to resist multiple antibiotics can be swapped and selected for, even if only one of the resisted antibiotics is being used.

This is all unavoidable, but is worsened by overuse of antibiotics or improper use of antibiotics, for example using a broad spectrum antibiotic instead of a targeted narrow spectrum drug. Resistance is also worsened when patients stop their antibiotic regimen prematurely allowing resistant bacteria to bounce back.

The worst-case scenario is that we will enter a post-antibiotic era where humanity is plagued by a host of completely resistant bacteria. Right now we are moving in that direction, as bacteria are evolving resistance faster than we are developing new antibiotics. The FDA has not approved a new class of antibiotics (one that works on a new target, rather than just a new version of an existing class) for almost thirty years (since the late 1980s). 

There are, however, several potential new antibiotics in the pipeline. One new drug is making headlines because of a recent Nature article publishing early research, and because of a novel mechanism of antibiotic discovery. The drug is teixobactin, which disrupts the cell membrane of some bacteria. It is potentially effective against gram-positive, but not gram-negative bacterial species.

There are two encouraging aspects of this research. The first is that the researchers, Lewis et. al. developed a new assay to screen for possible antibiotic compounds. Many antibiotics were discovered by culturing bacteria from soil to look for those that inhibited the growth of infectious bacteria (some bacteria produce compounds that inhibit the growth of other bacteria). However, only about 1% of soil bacteria can be cultured, and that pool has been mined long ago.

Lewis and his fellow researchers developed what they call an iChip which is capable of culturing the other 99% of soil bacteria. The chip contains hundred of little chambers containing soil that would allow for bacteria to be culture in their required environment. After the bacteria are cultured on the chip they are overlayed with a gel containing either Staphylococcus aureus or Mycobacterium tuberculosis (two bacteria that cause infections in humans). If a colony fails to form over one of the chambers, then the bacteria growing in that chamber may be producing an antibiotic.

They have already screened over 10,000 bacteria in this way, discovering many potential antibiotics, including teixobactin. This technique may therefore lead to the discovery of many new antibiotics.

The second reason for optimism is that, so far, none of the Staphylococcus aureus or Mycobacterium tuberculosis tested showed any resistance to teixobactin. This does not mean resistance will never develop, but hopefully it will mean the antibiotic will remain effective for at least decades.

The caveat here is that this is pre-clinical research only. The drug now needs to be tested in animals and then humans. Many potentially very useful drugs die at the early clinical stage because it is discovered they have some toxicity. Drug companies may still synthesize different versions of the drug, trying to reduce toxicity or change its pharmacological properties, and that could add many years to development with no guarantee of an approved drug at the other end.

There are three other antibiotics in the pipeline with novel mechanisms of action. One is brilacidin, which is described as a peptide mimetic, because it mimics a protein used by our immune system to attack bacteria. This drug is in early human trials, but is still several years away from approval if all goes well. The company, Cellceutix, claims the drug is broad spectrum, rapidly bacteriocidal, with a low potential for resistance.

There are also two new beta-lactamase inhibitors, avibactam (Forest Laboratories) and MK-7655 (Merck). These are also in early clinical trials, meaning that if all goes well they are 3-5 years from approval.

These new drugs are encouraging, but again there is no guarantee any of them will make it through the research process.


The evolution of bacterial resistance is a major problem for our civilization. I know we face many challenges, and this is just one, but every expert I talk to or read seems to be expressing the same opinion – this is very serious and we are not paying enough attention to this problem.

We need to continue to improve standard practice in terms of antibiotic use to minimize resistance, to educate the public about the importance of proper antibiotic use, and to research novel mechanisms for fighting bacterial infections.

The situation is not hopeless. We just need to keep ahead of the curve. At some point we may need to take existing antibiotics off the shelf and allow resistance to fade so that we can then cycle them back in the future.

As with many of these long term problems facing our civilization, we need to start thinking in terms of a sustainable strategy. There may always be game-changing technology in the future, but we can’t predict or count on such technology, so for now we need a sustainable solution.

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