“The Tao of antibiotic development is to balance three factors: target specificity or activity; druggable properties, which include the ability to synthesize, manufacture, and deliver the drug into the body; and pharmacokinetics, particularly off-target toxicity.”
Antibiotic resistance is a serious and growing problem in modern medicine and it is emerging as a preeminent public health threat. Each year in the United States alone, at least two million people acquire serious infections with bacteria that are resistant to one or more antibiotics, and at least 23,000 people die annually as a direct result of these antibiotic-resistant infections (CDC 2013). In addition to the toll on human life, antibiotic-resistant infections add considerable and avoidable costs to the already overburdened U.S. health care system. Studies have estimated that, in the United States alone, antibiotic resistance adds $20 billion in excess direct health care costs, with additional costs to society for lost productivity as high as $35 billion a year. The overuse of antibiotics is the single most important factor leading to antibiotic resistance. According to the Centers for Disease Control and Prevention (CDC), “up to 50 percent of all the antibiotics prescribed for people are not needed or are not prescribed appropriately.”1
At its September, 2012 meeting, the Chemical Sciences Roundtable (CSR) heard two presentations highlighting the need for new medications to combat the growing threat. These presentations also described some of the current challenges facing antibiotic development and some of the possible solutions to overcome those challenges. To better understand these important topics, the CSR held a workshop on September 23, 2013, in Washington, DC. The workshop explored the challenges and some approaches in overcoming antibiotic resistance, screening for new antibiotics, and delivering them to the sites of infection in the body. The workshop also conducted discussions about possible future endeavors that the field might take to develop the next generation of potent antimicrobial compounds capable of once again tilting the battle against microbial pathogens in favor of humans. In introductory remarks to the workshop, Carole Bewley, of the National Institute of Diabetes and Digestive and Kidney Diseases and a member of the workshop organizing committee, explained the purpose of the workshop in this way: “The goal here today is to give representatives from industry, government, and academia a broad view of the landscape of antibiotic development and the technological challenges and barriers to be overcome.”
This workshop summary is organized into five chapters. This chapter recounts the overview of the antibiotic resistance problem presented by Rose Aurigemma of the National Institute of Allergy and Infectious Diseases (NIAID). Chapter 2 discusses some of the challenges researchers face in developing novel antimicrobial agents that overcome resistance. Lynn Silver, a consultant at LL Silver Consulting, LLC, discussed the need to select drug targets that are not subject to rapid resistance selection, and Shahriar Mobashery, of Notre Dame University, spoke about the mechanisms that bacteria use to neutralize many of the most potent antibiotics.
Discovering new antimicrobial agents requires screens to identify compounds that can serve as starting points for additional development; Chapter 3 discusses some of the challenges involved in developing suitable screens for compounds whose mechanism of action would make them unlikely to trigger resistance, bypass resistance mechanisms, or directly counter the pathways that produce resistance. Karen Shaw, of Cubist Pharmaceuticals, presented some advice on how to conduct screening and described some of the pitfalls based on knowledge accumulated in the pharmaceutical industry. Chaitan Khosla, of Stanford University,
1 Press Release: Untreatable: Report by CDC details today’s drug-resistant health threats. Centers for Disease Control and Prevention, September 16, 2013.
spoke about the approaches that he believes have a chance of reviving the discovery of new natural antibacterial agents. Chapter 4 focuses on challenges in drug delivery, with J. Rubén Morones-Ramírez of the Universidad Autonóma de Nuevo León discussing some of the different tacks that he has taken to define and deliver novel antimicrobial therapies and Mark Smeltzer of the University of Arkansas for Medical Sciences addressing the issue of overcoming the physical barrier created by biofilms. The final chapter recounts some of the key messages presented during the workshop.
Although not comprehensive, this summary provides the readers with an overview of several topics discussed at the workshop:
- The challenges in overcoming antibiotic resistance.
- The difficult task of identifying targets for drug development and screening chemical libraries for new chemical entities that can surmount resistance.
- The need to develop methods for bypassing biophysical barriers that impede delivery of antimicrobial agents to the sites of infection in the human body.
- The path forward to increase the generation of new antibiotics.
This summary does not contain any findings or recommendations related to these topics, as this was not part of the workshop’s task. This summary describes presentations given at the workshop and the views expressed by workshop participants. As the workshop was limited in the time available to cover a very broad topic, it was therefore decided to cover only a subset of issues and questions facing the current state of antibiotic discovery and development in general terms. There clearly remain myriad specific issues and questions that were not discussed or presented during the workshop, and therefore are not included herein.
To start her overview of the antibiotic resistance landscape, Rose Aurigemma, Section Chief for Drug Development at NIAID at the National Institutes of Health (NIH), stated the concern among infectious disease specialists that medicine may be on the verge of returning to a pre-antibiotic era in which there will be important human pathogens that no longer respond to any available antibiotic, and she noted the timeliness of the CDC’s new report Antibiotic Resistance Threats in the United States 2013. She said that there are three organisms for which the situation is considered urgent—Clostridium difficile, carbapenem-resistant Enterobacteriaceae (CRE), and drug-resistant Neisseria gonorrhoeae—as well as a dozen organisms for which the threat of antibiotic resistance is currently considered to be serious (Figure 1-1).
Forty-three of 50 states have reported confirmed cases of CRE, as have countries throughout much of South America, Western Europe, and Asia. CRE results from the presence of various enzymes that cleave the lactam ring in carbapenem antibiotics and renders them ineffective. Given that carbapenems are currently an antibiotic of last resort, treatment overall becomes ineffective once resistance develops. The appearance of two specific enzymes in CRE—Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM)—are of particular concern.
Fluoroquinolone-resistant gonorrhea is a growing problem for which there is little awareness among the public, though NIAID has a significant research effort underway to combat this resistant organism. Because of the appearance of resistance, CDC changed its treatment recommendations for gonorrhea to move from fluoroquinolones to an intramuscular injection of cephalosporins such as cefixime and ceftriaxone. However, the incidence of resistance to those two antibiotics is also growing. “While [antibiotic-resistant gonorrhea] is not a deadly disease, it is a great public health concern,” said Aurigemma.
Resistance develops, Aurigemma explained, as an evolutionary response to the selective pressure of antimicrobial drugs, particularly when patients do not complete a prescribed course of therapy. Other factors include over-prescribing of drugs by physicians, the common practice of using broad-spectrum antibiotics when narrow-spectrum antibiotics would be preferred, and agricultural use in livestock. Common mechanisms of resistance include a change in drug target, such as when a bacterial enzyme undergoes a structural change to eliminate a drug binding site, or the appearance of a drug-metabolizing enzyme, as in the case of KPC and NDM. There can also be a change in drug access related to the appearance of membrane-bound efflux pumps that remove a drug from the organism as quickly as it enters or when microorganisms sequester themselves behind a biofilm barrier.
To counter these microbial responses, researchers are turning to the power of the ‘omics’—genomics, proteomics, metabolomics, and the like—to identify new drug targets beyond the well-known resistance factors. Examples include regulators of bacterial growth and pathogenesis and transcriptional regulators involved in processes such as sporulation, toxin production, and adhesion. Antibiotic developers are also attempting to better understand the chemistry of getting drugs into bacteria, a process that largely remains a mystery. Aurigemma said that there is some worry that target-based screening approaches have been exhausted and that the available chemical libraries have already been plumbed for the best drugs. “We need new ideas, new approaches to screen for drugs, and perhaps that’s where the ‘omics’ comes into play,” she said. There is some excitement in the field around natural products, but fully exploiting nature’s chemical libraries awaits improvements in both screening
FIGURE 1-1 The growing threat of antibiotic resistance.
SOURCE: CDC (2013).
and synthetic chemistry technologies. “These compounds are often difficult to manufacture,” she said, referring to potent naturally existing antimicrobial agents.
Aurigemma then discussed some nontechnical factors that are “getting in the way of good drugs.” A major reason is skepticism in the financial markets of the value of antibiotics. Large pharmaceutical companies have largely exited antibacterial agent discovery, instead focusing their attention on chronic diseases. In theory, that should open the door to smaller companies that, as she put it, “are more likely to think out of the box and come up with novel ideas and take a risk in trying new paradigms.” However, antibiotics traditionally fail early and often during development because of toxicity or formulation issues, reducing the appetite of the venture capital market to fund small companies during the discovery and early development phases of research. Federal support for early phase research and development is also in short supply these days, and uncertainty in the regulatory arena—the Food and Drug Administration (FDA) is developing new guidance for drug approvals and drug trials in order to meet this growing need for new antibiotics—further complicates the funding picture.
That said, Aurigemma noted that NIAID does have a comprehensive and sustainable research and development program feeding the pipeline with antimicrobial agents, including antibiotics. “Since pharma is not engaging in this research and small companies are limited in their resources, [NIAID] is trying to do as much as we can to support this effort,” she said, adding that CDC, FDA, the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Department are partners in supporting antibiotic development. In addition to supporting research, NIAID has also contracted with manufacturing facilities and has developed a network of clinical sites that can conduct clinical trials through phase II of the development process. One of NIAID’s goals is to lower the risk of drug discovery and development by using a range of funding mechanisms, including grants, cooperative agreements, contracts, and
small business innovation research awards, to take a potential new agent through phase II trials, at which point it expects the commercial sector to take over a project.
Complicating the antibiotic world are recent discoveries about some of the “collateral damage” that can accompany antibiotic use. For example, recent work has uncovered a correlation between the level of use of antibiotics, particularly among children, and the incidence of obesity in various regions of the country. At this point, some researchers believe that this correlation may be tied to changes in the gut microbiome caused by antibiotics. Much work is still needed on this and other areas related to gut bacteria however, this example illustrates one hypothesis and why more work is needed.
The Tao of antibiotic development, Aurigemma explained, is to balance three factors: target specificity or activity; druggable properties, which include the ability to synthesize, manufacture, and deliver the drug into the body; and pharmacokinetics, particularly off-target toxicity. She said the latter factor is particularly challenging because antibiotic toxicity is often poorly understood. “And that is why many researchers focus on known antibiotic classes because they know the toxicities and they know what they are up against in terms of showing that a new antibiotic is safe or that any toxicities are within the class of known toxicities,” she said. It is important to keep in mind that toxicity can arise from many mechanisms, including off-target binding and poor specificity.
After briefly reviewing the many known microbial targets for antibacterial development (Figure 1-2), Aurigemma noted that there are also host factors that could be targets for antimicrobial drugs. Intracellular pathogens, for example, could be susceptible to drugs that activate myeloid cells. It may be possible to identify the body’s natural antibacterial peptides, known as defensins; block the inflammatory pathways that trigger sepsis; or block the host receptor for bacteria and other pathogenic organisms. Another promising approach is to harness bacteriophages, the natural killers of bacteria. Investigators are also developing monoclonal antibodies and vaccines that could prove helpful in treating or preventing infection by antibiotic-resistant organisms.
Aurigemma concluded her remarks by stating that the solution to antibiotic resistance lies not just with developing better antibiotics. “You want better detection. Stewardship of antibiotics is important. So, too, is better control to stop the spread of infection,” adding that antibiotics have to be eliminated from animal feed, but acknowledging, too, that getting the food industry to agree to do so is going to be an uphill battle. “The fact that bacteria can mutate at such a rapid rate makes it challenging to keep ahead of them,” she said in closing. “But I do think we are on the right track for developing the tools, and especially the public mindset, to make progress.”
In response to a question about whether new diagnostic technologies that can rapidly identify specific strains with specific resistance patterns could lead to better use of narrow-spectrum antibiotics, Aurigemma said that this was indeed a promising area of research that could have a significant impact on how antibiotics are used. However, physician
FIGURE 1-2 Many of the known targets under investigation for antibacterial development.
SOURCE: Rosemarie Aurigemma (2013).
education will play a critical role in determining whether that in fact plays out in real-world use.
Responding to another question, she noted that live biotherapeutics2 are a promising avenue of research, particularly for Clostridium difficile infections. She also thought that combination therapy, where agents attack different microbial targets, could prove fruitful both in terms of therapeutic efficacy and avoiding the development of resistance. The challenge in developing combination therapies will be getting companies to work together on clinical development.
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CDC. 2013. Antibiotic Resistance Threats in the United States 2013. Washington, DC: Department of Health and Human Services. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf (accessed October 28, 2013).
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2 Live biotherapeutics refer to the use of bacteria or bacteriophage, as therapeutics for infection.