by Francesca Tomasi
figures by Aparna Nathan

Too Much of a Good Thing?

Ninety years ago, Alexander Fleming happened upon the chemical compound penicillin and sparked a medical revolution. It was a serendipitous occasion – Fleming had been growing plates of bacteria in his lab when he noticed some mold growing on one of them. Just some classic contamination, he probably thought, ready to discard it as useless for his research purposes. But upon looking more closely at that fateful petri dish, he noticed that wherever the mold grew, bacteria did not. Fleming had inadvertently found a natural antibacterial compound (streptomycin), and sparked a revolution in the treatment of many infectious diseases.

The notion that a “magic pill” could cure common infections in a matter of days energized the medical community and led to the discovery of even more antibiotics. Conditions such as strep throat, ear infections, or pneumonia were no longer a death sentence. The life expectancy of infants rose dramatically, and people euphorically spoke of eradicating infectious diseases forever. Yet the convenience of early antibiotics led to their overuse. Antibiotics were prescribed for all sorts of conditions – whether or not they would actually help.

In 2014, the World Health Organization (WHO) published its first global report on antibiotic resistance, stating that antibiotic resistance is “a serious threat [that] is no longer a prediction for the future, it is happening right now in every region of the world….” We have encouraged the evolution of drug-resistant bacteria faster than we can develop new antibiotic treatments.

To keep up with an ever-changing nemesis, antibiotic discovery in the twenty-first century must shift to the development of new classes of drugs and be coupled with deliberate policy programs designed to minimize the risk of resistance emergence and spread.

An Evolutionary Arms Race

Antibiotics work by either directly killing bacteria directly or by inhibiting bacterial growth, allowing our immune systems to clear the infection. Today, these compounds come in many forms and are classified by their mode of action (what do they target in bacterial cells?), chemical structure (how do they target what they target?), and activity spectrum (which bacteria are they effective on?).

Antibiotics can be broadly grouped into different classes. For example, the beta lactam class of antibiotics refers to over a dozen drugs that each inhibit the synthesis of bacterial cell walls. The cell wall of a microbe is essential for its survival and provides structural integrity as well as protection from the cell’s external environment. While each drug has different specific targets, beta lactams all kill bacteria in roughly the same way.

We are not the only ones who recognize antibiotics by class, though. Over time, bacteria have developed so-called beta lactamase enzymes, named for a ring they share in their chemical structure. Beta lactamases break this ring open and render antibiotic ineffective. If a beta lactam is a lock, a beta lactamase is a bolt cutter.

When beta lactam-resistant bacteria first emerged, scientists entered into an arms race. Once they understood how beta lactamase worked, they modified the chemical structure of existing beta lactams to make them no longer recognizable for destruction. As this proved to be an effective (albeit short-term) solution, drug manufacturers continued replacing the drug “lock” with something different to evade destruction, but over time, bacteria continued to produce effective bolt cutters. This can be explained by the fact that the underlying function of each beta lactam antibiotic was fundamentally the same. It’s like software updates: when software developers detect bugs in a system, they release updates to fix them. The core software is the same, just with modifications. With bacteria, drug manufacturers’ software updates were new beta-lactams. Bacteria then are able to modify their own biochemistry to sidestep our updates.

Every drug that enters the market costs several billion dollars, from research and development through testing. When antibiotic development proved to be the arms race described above, some of the biggest pharmaceutical firms – such as Pfizer, Roche, and Bristol-Myers – dropped like flies from antibiotic research.

The few companies that continued developing antibiotics on mostly focused on this so-called “analog discovery” – modifying the chemical structure of existing drugs just enough to bypass known resistance mechanisms, as with the beta-lactams. From a business perspective, this is safe: side effects and targets have already been classified, and approval processes will be faster. From an arms race perspective, however, this fuels antibiotic resistance by repeatedly introducing modified, but similar enough, drugs.

Can Government Incentives Help Companies Change Course?

As we have seen, bacterial physiology works in a “fool me twice, shame on me” way. Per the software metaphor , because we continued to release minor updates instead of re-designing the core software, the global antibiotic pipeline is now running dry.

Figure 1. Timeline of antibiotic production.

Only 15 new antibiotics have been approved since 2000, compared to the 63 put to clinical use between 1980 and 2000 (Figure 1). Out of these 14 new drugs, only 4 of them represent new classes of antibiotics, targeting bacteria through novel mechanisms. Linezolid, for instance, is the first “oxazolidinone,” and it entered the market in 2000. Oxazolidinones are considered last-resort drugs to be used only when every other existing antimicrobial therapy has failed. Still, bacteria resistant to each of these new drugs have already been isolated.

Discovering new forms of antibiotics to resolve this problem is a major challenge, but the longer it is ignored, the worse it becomes. To keep up with the evolutionary arms race between drugs and bacteria, antibiotic discovery should occur at least as quickly as resistance mechanisms emerge, and policy should reflect this urgency.

In 2012, Congress passed GAIN, the Generating Antibiotic Incentives Now Act. The law, signed by President Barack Obama in July of that year, formed the Antibacterial Drug Development Task Force and laid down financial incentives in exchange for turning industry back on to antibacterial research: lengthened drug-patent exclusivity and faster FDA approval processes. Lengthened drug-patent exclusivity allows for a company to produce antibiotics for five extra years on average with no generic manufacturing competition.

Policy researchers have found that similar programs around the world encourage drug development in the face of a major global health crisis. However, they note that most policies are focused on the early stages of discovery, and that there is little communication between nations on translating bench findings into the market. This poses a threat of duplicating efforts in the initial steps of antibiotic discovery, while overlooking the transition from the bench to the clinic. To address this, last year the United Nations established an Inter-Agency Coordination Group on Antimicrobial Resistance. The group’s purpose is “to ensure sustained effective global action to address antimicrobial resistance, including options to improve coordination.”

Moving Antibiotic Research into the Twenty-First Century

Dealing with antibiotic resistance requires the enthusiasm of Alexander Fleming’s time, which brought the world twenty new drug classes that served us for 60 years. But even if we do discover 20 more classes in the next 20 years, this is still only a generation-long solution.

Figure 2: New ways to kill bacteria. Scientists have been developing alternative ways to kill bacteria, such as the use of bacteriophages, polymers, and other kinds of engineered nanoparticles.

Discovering novel antibiotics will require creative, interdisciplinary approaches, some of which are currently underway (Figure 2). Scientists have been developing alternative ways to kill bacteria, such as the use of phages (viruses that kill specific bacterial strains), polymers (peptide structures that literally shear open bacterial cells without targeting a specific protein) and other kinds of engineered nanoparticles. Furthermore, researchers have developed new ways to discover antibiotics in nature, including one that led to discovery of a brand-new class of antibiotics. This compound, teixobactin, has not yet entered the market, though it shows promise.

With scientific efforts gaining momentum, it is important to encourage communication between government, industry, and academic stakeholders. Financial and legislative efforts are necessary to move forward. This includes the resources to rigorously test novel compounds for safety and efficacy. This also includes policy focused on the prudent implementation of new regimens (such as antibiotic stewardship, which embraces education, tracking, and reporting of antibiotic use in hospitals), coupled with active monitoring for the emergence of resistance.

It all starts with a widespread appreciation for the burden of infectious diseases and their persistence as a leading cause of death worldwide. The unique position of antibiotics compared to other common drugs is one that warrants an additional layer of urgency: they become redundant over time, and until we figure something else out, we need the means to continually replace them.

It’s time for less of the same, and more of the new.

Francesca Tomasi is a first year graduate student in the Biological Sciences in Public Health PhD program, studying tuberculosis antibiotic resistance and drug targets in Eric Rubin’s lab.

For more information:

An article in The Journal of Antibiotics about incentivizing innovation in antibiotics research.

More about the history of antibiotic discovery.

SITN article about bacteriophage as an antibiotic alternative.

More about the science behind antibiotic resistance.

 

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