Can We Outmaneuver the Superbugs?
Microbial Solutions
Regina Kelder

Can We Outmaneuver the Superbugs?

NIH program officer Jane Knisely talks about some of the novel research approaches aimed at antimicrobial resistance

Ten months ago, US President Barack Obama signed an executive order prioritizing efforts to combat the rise of antibiotic-resistant bacteria, and released a national strategy on how to identify priorities and coordinate investments. These include preventing, detecting and controlling outbreaks of resistant pathogens recognized by the US Centers for Disease Control and Prevention (CDC) as urgent or serious threats, such as carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), ceftriaxoneresistant Neisseria gonorrhoeae, and Clostridium difficile (C. diff.)

More recently, the White House released a five-year action plan that outlines federal Jane Kniselyactivities to prevent and contain outbreaks of antibiotic-resistant infections, ways to maintain the efficacy of current and new antibiotics and strategies to develop and deploy next-generation diagnostics, antibiotics, vaccines and other therapeutics.

The National Institutes of Health (NIH), the largest public funder of biomedical research in the world, is central to this effort. A 15-page report released last year by the National Institute of Allergy and Infectious Disease (NIAID) outlined some of the novel approaches the agency is taking to meet this public health challenge. These strategies include the use of systems biology to examine molecular networks of host-pathogen interactions and global changes in response to drug exposure and harnessing the immune system to combat bacterial infections. NIAID-funded research is also exploring ways of targeting bacterial virulence without directly killing the bacteria, using phage or phage-derived lysins to kill specific bacteria and making synthetic microbiota to mitigate infectious diseases.

There is hope that some of these novel approaches will curb the significant human and financial costs of antimicrobial resistance. The US Centers for Disease Control and Prevention in Atlanta estimates that drug-resistant bacteria cause 23,000 deaths and 2 million illnesses each year in the United States. Antibiotic resistance also threatens animal health, agriculture, and the economy.

Eureka recently reached out to Jane Knisely, who oversees studies of drug-resistant bacteria supported by the NIH, to learn more about this public health problem and what scientists are doing to address it. The interview was conducted by Senior Scientific Writer Regina McEnery and Communications Coordinator Michael Migliaccio.

Are drug-resistant bacteria a growing problem or a static one?

JK: It's definitely a growing problem. Particularly in the past 15-20 years there are certain types of bacteria that have been acquiring resistance at a really rapid pace to the point where we are out of or almost out of treatment options for them. With the multi-drug and pan-drug resistant strains of bacteria that have emerged we are fearful that we will risk disruptions of routine medical care like surgery, chemotherapy and transplants, all of which rely on the use of antibiotics to prevent and treat infections. On top of that there has been a decreasing pipeline of antibacterial drugs over the past several decades. What that has meant is that we no longer have treatment options coming online to help with these resistant infections, and so more and more physicians are being left with limited or no treatment options for their patients.

Do we know why certain drug-resistant strains develop resistance at a faster rate?

So the example I will give is kind of a broad class of bacteria called gram-negative bacteria. Within this category are a group of organisms you may have heard of called [CRE.] Those bugs naturally have the ability to take up DNA from external sources, from other bacteria for example. Some of these bacteria have accumulated small bits of genetic information that code for many, many different resistance factors that resist drugs in different ways. They may have a resistance efflux pump that pumps drugs from the cell, or they may have beta-lactamases which chew up the drugs, or they may have mutations in the target site of the drug. In particular, these gram-negative bacteria are all good at sharing these smart ways that they have to resist drugs.

Has this rapid rise in gram-negative resistant strains been occurring over time or is it a fairly recent phenomenon?

It may have been occurring gradually over time, but we just didn't pay as much attention because we always had new drugs to turn to. Advances in medical treatment, where we are able to prolong lives much longer than we could in the past, and the prevalence of immune-compromised patients, insertion of indwelling catheters and central lines, also provide a breeding ground for the spread of these organisms. And then there are things like Acinetobacter baumannii, where the rise in resistance has been extremely fast. This has to do with infections that were contracted by the military in Iraq and Afghanistan, where those bugs are more prevalent. It was present in hospitals here before, but since those conflicts and the return of wounded soldiers who needed long-term care it has become more prevalent and acquired more resistance.

What are some novel approaches being explored to combat antimicrobial resistance?

Many are focused on ideas that are kind of a departure from the small molecule antibiotics that have been used in the past. One of them is phage therapy, which uses bacteriophage—natural predators of bacteria that have very specific host ranges of the types of bacteria that they can infect and kill—to combat certain types of pathogenic bacteria. It's an idea that has been around for an extremely long time and is still used today in parts of the former Soviet Union and in Poland. Another example is manipulation of the microbiota. The human microbiome is the collection of microbes that live in and on us. What we are finding, especially through the study of C. diff., is that the microbiome perturbation that happens when broad spectrum antibiotics are given is actually responsible for the ability of C. diff. to come in and colonize. In clinical practice there was a finding that performing a fecal transplant—taking stools from a healthy donor and putting it into a person infected with C. diff.— could actually cure C. diff. with very high success rates. And so what some of our scientists are doing is to try and translate those findings into something that is a little bit more of a tractable product and also to evaluate whether there are other ways that that same premise can be used for other types of infections.

How are genomic technologies being applied in the study of microbial resistance?

Primarily through genomic mining of some of the soil bacteria that have been good sources of antibiotics in the past—looking for sequences that signal it has an antibiotic-like property. The other really interesting thing that NIH-funded researchers have done and are doing is mining different environments, sometimes extreme environments, for new sources of microorganisms and then screening those for new products that they produce that have antibacterial activity. That is not so much using genomic technology but actually taking microbes that we either have never screened before or taking samples from sources that have been mined and putting those samples into an environment where some of the microbes that are not able to grow on typical media can grow.

How about combination drug therapies?

Combination therapies are probably likely to increase as we lose more and more drugs. There was a recent FDA approval of a drug, Avycaz™, that is a combo product. It is a beta-lactam antibiotic, which is the same class as penicillin, paired with a beta-lactamase inhibitor. Beta lactamases are enzymes that bacteria produce that destroy antibiotics. And so having that inhibitor means the antibiotic can still work on the bacteria and is not destroyed. [Avycaz™] was an exciting approval because it was for a new drug to treat gram-negative infections and CRE in particular. That was the first one that had been approved in quite some time that had that spectrum of activity.

How to cite:

McEnery, Regina and Magliaccio, Michael. Can We Outmaneuver the Superbugs? Eureka blog. Jul 14, 2015. Available: