About 23,000 deaths due to approximately 2 million infections by antibiotic resistant bacteria occur each year in the US. Additionally, failed antibiotic treatments result in an estimated $20 billion spent on health care. The bacteria that cause these deaths have been called “superbugs.” Most recently, 7 deaths from “superbugs” at a UCLA hospital were spread from patient to patient through endoscopes that were not yet FDA approved. The media has been using the term “superbug” for years now, but what does it even mean?
In the mid 90s, the term “superbug” was used sporadically in peer reviewed journals. Notably, these articles highlighted emerging antibiotic resistance in strains of E. coli, Streptococcus, Enterococci, and importantly Staphylococcus. Methicillin resistant Staphylococcus aureus (MRSA) emerged only one year after the first use of methicillin as an antibiotic in 1959. MRSA is now one of the most widespread pathogens and common causes of hospital acquired infection. As a result of methicillin resistance, one of the antibiotics most widely used to treat MRSA in the 90s was vancomycin.
In 2002 in Michigan, one of the first reports of vancomycin resistant MRSA, now dubbed VRSA, came to light. An article in Nature used to term “Superbug” to describe the vancomycin resistant organisms. Now superbug is commonly used by the media to describe any variety of antibiotic resistant bacteria. Unfortunately “superbug” is not descriptive, and has been used to headline deaths by not only MRSA, but also antibiotic resistant strains of Klebsiella pneumoniae, Clostridium difficile, Acinetobacter baumannii, Mycobacterium tuberculosis, to list a few of the dozens.
There are several classes of antibiotics, each which exert their antimicrobial action in a different way. Similarly there are several different mechanisms by which antibiotic resistance occurs. For example, aminoglycoside antibiotics are able to bind to and block the bacterial ribosome, which effectively inhibits or alters bacterial translation, resulting in cell death. Some bacteria have acquired genes that encode proteins that can bind to and modify these aminoglycoside antibiotics. Modification of the aminoglycoside renders it inert, and unable to kill the cell. Several classes of antibiotics are shown in the figure above, along with a few mechanisms of resistance. “Superbug” doesn’t describe the type of bacterial infection, nor does it inform about the mechanism of resistance.
Only 12 FDA approved antibiotics have been developed since 2000. In the 90s, 20 antibiotics were FDA approved, and 43 in the 80s. The steady decrease in antibiotic development is a result of several compounding factors.
1) A new drug takes an estimated 10 years to develop from scratch. Most drugs fail at some point between initial discovery, in vitro testing, animal testing, and clinical trials.
2) Drugs are expensive to develop. If you want a profit you make a drug that people take for life, not week like most antibiotics. This ties into point 3.
3) Antibiotic resistance is often detected within years of its initial use in the clinic. Therefore the time an antibiotic is actually relevant and useful is relatively low compared to drugs that treat arthritis or cardiovascular disease.
4) The low hanging fruit have been harvested, and nobody wants to pioneer the more difficult work. A majority of the antibiotic research presented at conferences, such as ICAAC, deal with betalactamases. The first antibiotic to be discovered, penicillin, is a betalactamase antibiotic. Dozens of investigators flocked to study the betalactamases after penicillin’s discovery. Graduate students and trainees from those labs then went to start their own labs, doing research on betalactamases. And now 50 years down the line, despite having a dozen classes of antibiotics, a majority of the antibiotic-focused academic labs study betalactamases. It’s easy to study betalactamases because it’s what we’ve been doing for half a decade. Moving forward is easier when the foundation is already set.
A recent article in Wired emphasized the need for more spending in the field of antibiotics. Only 1.2% of all funding from the NIH goes toward antibiotic resistance. The NIH budget has remained stagnant in the last decade, with a whopping 0.5% increase for 2015 to a grand total of ~$30 billion. To put this in perspective: The total federal budget in 2014 was ~$3.5 trillion. We don’t just need more money going toward antibiotics. We need more money going toward research in general.
Antibiotic resistance is and will continue to be a key issue in the years to come. Many pathogens have been dubbed “super-bugs” as a result of their ability to persist in the presence of multiple antibiotics. Some bacterial pathogens, like totally drug-resistant tuberculosis, MRSA, Klebsiella pneumoniae, and Acinetobacter baumannii are of particular interest because of their clinical prevalence and ability to quickly acquire drug resistance.
One primary concern with antibiotic resistance is the lack of new drug development. The median cost of developing a new drug is $4.2 billion dollars (forbes article), and without proper antibiotic stewardship, a drug may only be useful for 2 or 3 years. That’s not much return on investment. Big pharmaceuticals will not dump money into a drug without the prospect of long term revenue.
However, there are novel ways to tackle the issue of antibiotic resistance without the billion bucks. The most heavily researched mechanism of antibiotic resistance is mediated by a class of enzymes called betalactamases. 80% of the research in the field of antibiotic resistance has been focused on betalactams, and we seem to have forgotten that there are several other classes of antibiotics that we can play with. I discussed the problem of such heavy focus on one antibiotic here: Gripes with antibiotic resistance research.
Bacteria have gained resistance to every class of antibiotics including aminoglycosides, tetracyclines, quinolones, and polymyxins. Each method of resistance is typically granted by an enzyme, and these enzymes should be new drug targets. If we can inhibit an enzyme that grants resistance, then by coupling the new drug with an old antibiotic, we can reutilize obsolete antibiotics.
Another method that has recently gained traction is the inhibition of virulence factors. Most bacteria are not virulent, and incapable of infecting humans. Remember, the human body is an incredibly harsh environment for a microbe. However, those that are virulent typically carry genetic determinants that give them the ability to colonize a host. For example, Escherichia coli is a commensal bacteria of the human gut, but some strains have gained the ability to produce toxins or adhere to particular mucosal surfaces, making these strains virulent. The development of new drugs to inhibit virulence may be able to prevent disease. I briefly described one such method in Dealing with antibiotic resistance through anti-virulence factors, where inhibition of a toxin leads to survival of mice and protection from disease.
One process that can be considered a virulence factor is quorum sensing, a mechanism for bacteria to detect population density. Bacteria excrete peptides that they also have receptors for, and when the concentration of bacteria increases, so too does the excreted peptides. When the population reaches a particular concentration, gene expression changes and may induce virulence factors. Pseudomonas aeruginosa and A. baumannii are opportunistic human pathogens, and through quorum sensing are able to coordinate the formation of biofilms, a virulence trait. Inhibition of the quorum sensing may inhibit the progression of disease, and a method for discovering drugs that can inhibit this system is described in this paper published this month in PNAS: A high-throughput screen for quorum-sensing inhibitors that target acyl-homoserine lactone synthases.
The growing issue of antibiotic resistance is critical to global health, but the problem is still just a pea under a mattress and not enough attention has turned its way. Translational research and drug development are absolutely integral to advancements in the biomedical sciences, but basic research will give insight to novel drug targets and molecular mechanisms that we can utilize to cure disease. The pre-antibiotic era and the days where a common strep-throat or UTI would kill you are gone. However, without progress in research, stewardship, and activism, we could certainly regress.
This morning, a paper was published in mBio titled Inhibition of LpxC Protects Mice from Resistant Acinetobacter baumannii by Modulating Inflammation and Enhancing Phagocytosis. This is AMAZING. So I decided to put it in layman terms so those unaware may become interested. It’s a bit long, but I promise an interesting read.
Most, if not all, antibiotics used to treat septicemia target essential bacterial proteins, leading to either bacterial cell death or stasis and the prevention of cell growth. This then leads to the rapid clearing of the infection, saving the patient. However, in the case of Acinetobacter baumannii and many other opportunistic infections such as Pseudomonas or Staph, drug resistance has quickly spread and the fear of totally drug resistant (TDR) pathogens has become a reality.
A. baumannii is a beast. Several strains have become resistant to every antibiotic we have, including our last line of defense Colistin, or Polymyxin E. (Side note: the use of polymyxin was previously avoided except as a last resort due to its toxicity.) But the mechanism by which A. baumannii kills its victims is tricky. A. baumannii produces a lipopolysaccharide (LPS), specifically Lipid A , that is recognized by toll-like receptor 4 (TLR-4) on our immune cells. After the immune system sees the LPS, it begins to produce a storm of cytokines and interleukins, triggering a cascade of events that activate several other features of the adaptive and innate immune systems telling it that something has invaded. Basically, the recognition of LPS causes the immune system to kick into overdrive. The immune system’s overzealousness eventually causes hypothermia and a slurry of symptoms, leading to the death of the patient. Seems counterintuitive doesn’t it?
Normally, after the immune system sees LPS it recruits antibodies and macrophages to quarantine and kill the bacteria with the LPS. In the case of A. baumannii, the bacteria overproduce LPS, and actually shed it, leaving a trail of LPS wherever it goes. The immune system constantly runs into the LPS, believing it to be bacteria, causing a cytokine storm and hyperactive immunity. For this reason we call LPS an endotoxin because of its toxicity to humans and is considered a virulence factor because of its ability to cause disease.
What this paper first demonstrates is that in mice with a defective TLR-4, meaning they cannot recognize LPS, the mice no longer have disease and can survive for much longer when infected with A. baumannii. The paper only shows up to 28 days, but 100% of the TLR-4 knockout mice survived through the infection. Granted, these mice can no longer mount an immune response against the bacteria, but the disease has been cured!
Furthermore, the authors investigated the use of a drug, LpxC-1, that inhibits the synthesis of LPS in A. baumannii. In theory, this drug will block the shedding of LPS, and prevent the cascade of immune response, preventing the disease and eventual death. The first important piece of information is that this drug does not inhibit A. baumannii growth. The drug is not a classic antibiotic, and does not kill the bacteria nor slow their growth. The authors found that the drug was able to prevent death of the mice, even though these bacteria were still coursing through their veins. Even more profound, is that LpxC-1 actually promoted the phagocytosis of the cells by macrophages, leading to a lower bacterial density in the mice.
This paper has some absolutely amazing results, and some fantastic figures and images of the histopathology of A. baumannii in mice. This is very promising work that may lead to new classes of antibiotics that treat the actual cause of disease rather than directly targeting bacteria. The ability of bacteria to readily evolve mechanisms of drug resistance through selective pressures of classical antibiotics leads us to shy away from those traditional antibiotics.
The paper, linked above, is an incredible read and I would recommend it to anybody in the biomedical sciences, and perhaps even those outside of the sciences. The journal is open source, and although the figures are public I have not included them in hopes that you will read the paper to investigate it yourself.
Thanks ASM, I enjoyed attending my first Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Getting out of the lab was enjoyable, but upon hearing all the talks about antibiotic resistance I became more anxious with getting back to the lab. But you know what grinds my gears? Why all the concern with betalactamases?!
Outside of virology and fungal disease, I would estimate that 80% of all the posters and presentations were either NDM-1, OXA, BLA, or ESBL related. We have developed numerous classes of antibiotics outside of penicilins and carbapenems, and yet we focus so much of our attention on this single class.
I don’t refute that betalactam antibiotics were once an incredible tool for treating nosocomial infections. But our obsession with these antibiotics seems to be hindering forward progress. Therapy is already so limited when treating Klebsiella, Acinetobacter, or Pseudomonas, and as soon as colistin resistance becomes more prevalent, we’re done for. Didn’t we learn not to put all of our eggs in one basket? ESBL’s (Extended Spectrum Betalactamases) are a prime example of how we jam packed our basket with eggs.
I propose that we focus on other classes of antibiotics; macrolides, tetracyclines, quinolones, aminoglycosides, etc. Resistance to these antibiotics may be enzyme mediated, and although various inhibitors have been found for betalactamases, few, if none, have been found for those that mediate resistance to the other classes of antibiotics. We can improve therapy options for patients if we expand our areas of research.
Come on microbiologists. Get out of your ESBL studying niche, lives are at stake.