As humanity tallies the growing cost of Covid-19 in lives and capital, it must address the Grey Rhino threats posed by pathogenic bacteria. These are probable and impactful, but we neglect them despite their obviousness. Aided by modern humans’ mobility and by climate change, bacterial pathogens endanger everyone’s health. They are legion, varied, and constantly mutating. How can we best combat them?
- Pathogenic bacteria cause epidemics and pandemics
- Bacteria mutate to become resistant to antibiotics
- Antibiotic-resistant (AR) bacteria spread in communities and healthcare settings
- Discovery and development of new antibiotics are insufficiently incentivized
- Governments, industry, and academia must collaborate to bring new classes of antibiotics to the clinic
Mutating Bacteria Are On The Move
The germs of some of history’s worst pandemics, bacteria still imperil human health on a massive scale. Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, has afflicted humanity for millennia. Twenty-five percent of the world’s population may carry a latent form of the disease. Killing 1.5 million annually, it is the leading cause of infectious disease death. Strains of Mycobacterium tuberculosis have mutated to become resistant to many or all antibacterial drugs.
The aptly-named Yersinia pestis caused the Bubonic plague, which ravaged Eurasia and Africa, periodically flaring into catastrophic pandemics between the 6th and 19th centuries CE. It remains in animals and still spreads to humans in places as diverse as Mongolia, where it appeared in May, and New Mexico, where it surfaced last week.
Yersinia pestis is an example of the Gram-negative variety of bacteria, which includes scary-sounding organisms such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Salmonella typhimurium, and Escherishia coli. These can be difficult to treat because their elaborate outer barriers protect them from many drugs. Infection by Gram-negative Borrellia burgdorferi, the cause of Lyme disease, often goes undiagnosed and can cause diverse and potentially devastating symptoms if not treated early. Gram-negative Vibrio cholerae can produce a toxin that causes patients to produce copious diarrhea, thereby facilitating its dispersal and transfer to other hosts. The resulting disease, cholera, has plagued humanity for centuries.
Gram-positive bacteria, which include pathogens such as multi-drug resistant Staphylococcus aureus (MRSA), have less-complex surfaces than their Gram-negative cousins but are protected by thick cell walls. Clostridioides difficile, which can cause life-threatening diarrhea, is a naturally antibiotic-resistant Gram-positive bacterium. It can survive on surfaces for extended periods and can proliferate in patients’ digestive tracts, resulting in significant debility and death.
Bacteria have developed ways to pump antibacterial drugs out of themselves, destroy antibiotics that successfully penetrate them, and otherwise evade antimicrobial molecules. Bacteria are capable of exchanging and collecting genes that encode these drug resistance and virulence mechanisms, thereby acquiring, in some cases, imperviousness to all antibiotics previously used to treat them. Unprecedented human travel and globalization have enabled bacteria from one place to take hold in another. For example, Acinetobacter baumannii, a naturally antibiotic-resistant pathogen to which hospitalized, immunosuppressed patients are susceptible, is endemic to Eurasia, but has spread to North America.
Neisseria gonorrhoeae, the bacterium causing the sexually transmitted disease gonorrhea, has developed such worrisome antibiotic resistance that the NIH has prioritized investigating new ways to treat it. Bacterial pathogens are on the move across the globe and are evolving ways to resist antibacterial drugs.
For a patient infected with bacteria that respond to treatment, the impact of their illness is often a minor inconvenience. When antibiotic drugs are ineffective, or if one is immunocompromised (common for cancer patients and the elderly), hitherto innocuous infections can become life-threatening. Death certificates and obituaries sometimes refer to people dying of “complications” secondary to another medical condition. These “complications” are frequently the effects of infection by antibiotic-resistant bacteria. Why are they not always candidly reported? Under the 2010 Affordable Care Act, healthcare-associated infections (HAIs) trigger reduced Medicare reimbursements to hospitals. Perversely, those institutions which are most candid about reporting HIAs are most likely to be punished, leading to an undercounting of deaths caused by bacterial infections. This unintended consequence reduces the perceived demand for new antibiotics. At the same time, increased antibacterial stewardship by physicians — the practice of using new and last-resort drugs only on appropriate antibiotic-resistant pathogens to reduce the probability of bacteria evolving additional resistance — limits the actual market size.
The cost of turning an antibacterial molecule that kills bacteria in a Petri dish into an approved drug is conservatively estimated to be around $1 billion, an amount difficult to recoup in the present market and regulatory conditions. Not surprisingly, pharmaceutical companies large and small have discontinued their antibacterial drug programs in the past few years, among them Novartis, Achaogen (which filed for bankruptcy), and Melinta (which filed for bankruptcy but subsequently secured funding to attempt a comeback). Between 1990 and 2019, 78% of major drug companies have reduced or eliminated antibiotic research. Some startups pursuing antibacterials have pivoted away from infectious disease research to survive. A genuinely novel class of antibacterial drugs, dissimilar in chemical structure to current types of antibiotics, has not been developed in more than three decades.
Incentivizing Symbiotic Solutions
Academic research, primarily funded by governments, drives much of antibacterial drug discovery. University scientists’ focus and long timelines make them well-suited to elucidate the details of pathogens’ biology. However, academics’ ability to steadily pursue their research is imperiled by systemic dysfunctions in funding processes. Despite press releases touting the therapeutic potential of their scientists’ work, universities are not equipped to develop pharmaceuticals. Few possess the resources necessary to turn molecules discovered in their laboratories into safe and effective drugs. Moreover, university scientists face pressure to be the first to publish novel findings in high-profile journals. Such incentivization discourages them from performing the derivative research necessary to develop drugs, and may partially explain why pharmaceutical companies cannot repeat nearly 80% of academic laboratories’ biological studies.
Unlike universities, companies are optimized to apply and extend academic research to make drugs. As we have seen, daunting scientific and commercial hurdles have caused several companies to shutter their antibiotic programs. Alarmed by this, governments have taken notice. The U.K. commissioned a landmark study on antimicrobial resistance in 2016, which informed an extensive 2019 review by the U.S. Centers for Disease Control and Prevention. In January, the World Health Organization published additional research and policy recommendations. Charities such as the Wellcome Trust and The Pew Charitable Trusts have also commissioned extensive analyses. In the U.S., the GAIN Act (2012) sought to incentivize antibiotics’ development by extending the exclusivity period of drugs targeting specific pathogens. This intervention fell short of expectations, in part because it caused companies to develop new antibacterials that are chemically related to existing ones. This similarity makes these drugs susceptible to pathogens’ evolving resistance mechanisms. The draft DISARM Act, authored in 2019 by Senators Bob Casey (D-PA) and Johnny Isakson (R-GA), seeks to better incentivize the discovery and responsible use of new antibacterial drugs by changing how Medicare reimburses health care providers for their use.
Academia, industry, and the public sector each bring distinct resources to bear on the problem of creating antibacterial drugs. It is in humanity’s interest that we equip each of these symbiotic parts of an overarching effort to contribute its best work. The Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), which provides non-dilutive funding to offset the costs of antibacterial discovery through Phase 1 clinical trials, exemplifies such symbiosis. CARB-X, funded by governments and philanthropic organizations, collaborates with the Bill and Melinda Gates Foundation and is hosted by Boston University. Since 2016, it has disbursed $240 million to several startups, including Entasis and Ventoryx, to help them pursue antibacterial drug discovery programs. CARB-X plans to invest an additional $260 million by 2021.
To assist small companies in developing antibacterial drugs, a consortium of pharmaceutical companies recently established the AMR Action Fund. This entity plans to spend $1 billion to help bring two to four new antibiotics to the clinic by 2030. Moreover, it intends to build an alliance of stakeholders to encourage governments to create conditions favorable to sustainable antibacterial discovery and development.
A “Manhattan Project” to Fight Antibiotic-Resistant Bacteria
Organizations like CARB-X and the AMR Action Fund provide critical assistance in the battle against bacterial pathogens. Given that bringing a single antibiotic from concept to clinic costs $1 billion, and given the need for many new drugs, we must make much more significant investments.
During World War II, the U.S. Office of Scientific Research and Development (OSRD) built an academic-pharma collaboration to develop penicillin into a mass-producible drug. The OSRD provided oversight, logistical support, and funding for that successful effort. In the context of the Covid-19 pandemic, there have been calls to organize a similar project to address the threats posed by infectious diseases. Before the present disaster ends and complacency returns, policy-makers should establish an unprecedented campaign to combat pathogens, including antibiotic-resistant bacteria. It should be given funds and priority equivalent to those devoted to World War II’s Manhattan Project. Humanity is fighting a war against infectious disease. We must rebuild and expand our arsenal.