At the turn of the last century, Paul Ehrlich, a German scientist coined the term “magic bullet” to describe a novel way of treating infections. Ehrlich, who was also a physician, was looking for chemicals that would stain specific microorganisms and make them more visible to the naked eye, and he reasoned that if a drug could be made to selectively target a disease-causing organism, such as streptococcus, then a toxin for that organism could be delivered along with the agent of selectivity.

These observations, which earned Ehrlich a Nobel Prize for his contributions to immunology, helped set the stage for the Age of Antibiotics, a golden era that began with Alexander Fleming’s discovery of penicillin and grew to include drugs for all kinds of gram-negative, gram-positive and mycobacteria.

Flash forward several decades. Today, we are living in a kind of post-antibiotic age, where overuse and misuse of antibiotics have led to the rise of superbugs such as carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), ceftriaxoneresistant Neisseria gonorrhoeae, and Clostridium difficile (C. diff.) Around 700,000 people die every year from drug-resistant infections, according to one UK report and antimicrobial resistance is now evident in every country. Earlier this year, the Walter Reed Army Institute of Research characterized a transferrable gene for colistin resistance in the United States that may herald the emergence of truly pan-drug resistant bacteria. The first transferable gene for colistin-resistance was identified in November 2015 in China.

Last week, the UN devoted a full day of talks on antimicrobial resistance during its General Assembly in New York. It was only the fourth time in the UN’s 77-year history that health became the focus of a high-level meeting, indicating just how concerned countries are about this problem. Over 190 countries signed a declaration agreeing to combat antimicrobial resistance. How this will translate into meaningful actions remains to be seen, but new and novel antibiotics is going to have to be part of the solution.

Last year, Eureka spent time with Jane Knisely, who oversees studies of drug-resistant bacteria supported by the US National Institutes of Health, to hear about the research behind some of these newer approaches in drug development. We caught up with her again to hear how the work is progressing and to find out what’s new. Knisely, who spoke with Eureka a day after the UN talks ended, sounds cautiously optimistic. “This is only the fourth time that a health topic was taken up at that level,” said Knisely, referring to the UN session. “So it is definitely an historic time for this issue and there is a lot of momentum in the right direction. It really needs to go hand in hand with all the work that we in the agencies have been putting in place for years.”

Here is an edited transcript of our conversation.

Eureka: Are we making progress in advancing these novel strategies?

JK:  In the past couple of years, we have awarded a lot of targeted funding to combat antibiotic resistance. For example, this year we made six awards to study the systems biology of antimicrobial resistance. We also made five awards this year to develop host targeted therapeutics designed to limit antibacterial resistance. We also made over 20 awards for non-traditional therapeutics, which encompass synthetic microbiota, bacteriophage therapy, anti-virulence strategies and some host-targeted projects.

Eureka: Which ones are you most optimistic about?

JK: It is really very early to be picking which ones we think will yield the most exciting results, but I am just extremely glad that we are covering the waterfront and that we have a lot of new projects going in a  lot of new directions. Bacteriophage is one example where we are seeing a lot of interest and growth. A year ago we had just one project. We now have a number of different projects that we are using to try and generate data that hopefully will tell us if this very old approach can really work for the modern problems that we have.

Eureka: How do bacteriophages differ from conventional therapeutics?

JK:  Phages are natural viruses that infect bacteria. They target only one species or subset of strain, which has both advantages and disadvantages when you are trying to use them in a therapeutic context. Although there are places in the world where phages are used clinically, there is still a lot we don’t know about how they work and how they might be turned into products. That is where we [at NIH] are focusing our efforts. Interestingly, there are some phage products that are approved by the “food” part of the Food and Drug Administration and have been granted GRAS [generally recognized as safe] status. The phage is sprayed on different types of food, such as smoked salmon and lunch meats, to protect against food-borne bacteria. Using them in a therapeutic context is much higher bar, though.

Eureka: Can you describe some of these NIH-funded phage projects?

JK: Timothy Lu at MIT is working on engineering what is called a phagebody to use as an antimicrobial for CRE. The objective is to basically create and validate a platform for engineering phage-based antimicrobials that share a common scaffold. You then use phage to kill CRE without affecting other bacteria.

Eureka: What other interesting projects have surfaced in the past year to combat antimicrobial resistance? 

JK: CARB-X is a new biopharmaceutical accelerator launched in July focused on new products to combat antimicrobial resistance. The goal is to accelerate a diverse portfolio of at least 20 antibacterial products. CARB-X is leveraging up to US$250 million from Biomedical Advanced Research Authority (BARDA) with in kind support from NIAID and also has matching funds from Wellcome Trust. So it’s a global partnership. The NIH and BARDA also released details in September of a prize to develop innovative laboratory diagnostic tests that are trying to identify and characterize antibiotic resistant bacteria and to distinguish between viral and bacterial infections so that we can reduce the inappropriate use of antibiotics. There is a total of $20 million up for grabs for this project. 

Eureka: Are drug companies keen on developing new antimicrobials?

JK: Unfortunately, pharmaceutical companies continue to exit this space because it is not perceived to be profitable. There is a lot of effort to try and figure out what incentives we would need in order to encourage these companies to develop antimicrobial products. The NIH provides push incentives, which is money for R&D to de-risk candidates as they go through the discovery process. But what many people are calling for now are pull incentives, where a pharmaceutical company is rewarded at the end of the day when they develop and deliver a new antibiotic. Part of the rationale for that is that when we have a new antibiotic on the shelf, unlike most other drugs we don’t want to use it. This way, we can preserve the drug’s effectiveness so that it can be used to treat infections that are resistant to all the other existing antibiotics. That is one of the reasons this is not a profitable area. So there needs to be some other kind of incentive to help pull interest in developing new products. The long and short of it is that antibiotics represent a very low return on investment, especially compared to other therapeutic areas. We are relying a lot more on small and medium businesses to develop them.

Eureka: What makes the colistin case uncovered last year so scary?

JK:  It was an E. coli urinary tract infection, and while it wasn’t resistant to all drugs, it was resistant to colistin, one of our last-line antibiotics. Colistin resistance isn’t a new thing necessarily, but what is new or newly-discovered in this case is that it’s a plasmid-mediated colistin resistance. The gene is called mcr-1. In this case, the patient was treated effectively and is fine, but the concern is that if you get that gene along with other resistance genes that can also be shared on plasmids, you could wind up with a completely resistant isolate. That is why there was such a great deal of press.

Eureka: hat’s meant by plasmid-mediated colistin resistance?

JK: Bacteria have chromosomes where they carry genetic information. In addition, they carry one or more small pieces of DNA called plasmids. They can share those plasmids in a process called conjugation. Rather than a single clone, you are talking about a gene that is disseminating into multiple lineages of bacteria.

Eureka: What advice would you give global leaders about combating antimicrobial resistance?

JK: This is an incredibly huge problem and there many different facets to the response. The five goals in the US’s National Action Plan for Combating Antibiotic-Resistant Bacteria captures many of these facets. We need better surveillance, better stewardship, better diagnostics, better counter-measures for drugs and vaccines. We have to do all of those things. We need to use the drugs we have more wisely. We need to do a better job with surveillance and understanding the scope of the problem. We need to develop and implement better diagnostic tests. We need to develop better ways to treat drug-resistant infections. And we need to get international consensus. That is really key. The good news is that antimicrobial resistance is on the world stage and getting a lot of attention. You don’t get much bigger than the UN.

How to Cite:

McEnery, Regina. Bugs on the Run and the Hunt for Weapons to Stop Them. Eureka blog. Sept. 29, 2016.