Antibiotics: In Search of the Next Wonder Drug
In a world full of discussions around AI, gene therapy and robotic surgery, antibiotics may seem like relics of early medicine, but their pivotal role in modern healthcare cannot be overstated. In 1900, pneumonia, tuberculosis, enteritis, and diphtheria caused a third of all deaths, especially among children under 5. Early 20th century advancements in infection prevention such as surgical asepsis and water chlorination improved public health, but treatments were still limited. Existing “cures” like salvarsan and malariotherapy often had severe side effects and were only effective against a limited array of pathogens. This changed in 1928 with Alexander Fleming’s discovery of penicillin leading to the “golden age of antibiotic discovery” from around 1940 to 1960, during which numerous new antibiotics were developed.
The Snake that Ate Its Own Tail: Antibiotic Overuse Creates Resistance
As the field of antimicrobials was evolving, so were the bacteria, spurring an arms race between medical science and microbial adaptation in the form of antimicrobial resistance (AMR). Through genetic mutations and the exchange of resistance genes, bacteria can develop mechanisms to evade the effects of antibiotics and render existing treatments less effective. As an example, many antibiotics – including penicillin and its derivatives – exhibit a chemical structure characterized by a beta-lactam ring (in red).
This is important, as this structure reacts with components of the bacterial cell wall to, quite simply, destroy it. In response to widespread use of beta-lactam antibiotics, bacteria have developed enzymes called beta-lactamases, which cut open the ring before the antibiotic can exert its effect. Bacteria may also utilize efflux pumps to simply remove the drug from the cell before it kills them. As one class of antibiotic loses efficacy and another is brought in to take its place, pathogens may develop multidrug resistance. The World Health Organization (WHO) has identified antibiotic resistance as one of the biggest threats to global health today, with the potential to negate many of the gains of modern medicine over the past century.
Make New Friends, but Keep the Old: Innovative Strategies against AMR
In response to this threat, researchers are employing several innovative strategies to combat antimicrobial resistance (AMR). One approach involves the development of combination drug regimens to directly fight existing resistance mechanisms. One such method—currently being developed by groups such as the US company VenatoRx and researchers at the University of Tunis El Manar—is the use of beta-lactamase inhibitors to specifically target and disrupt the bacterial enzymes which provide resistance against existing antibiotics. Another tactic is phage therapy, which uses bacteriophages to infect and kill bacteria. The Biomedical Advanced Research and Development Authority (BARDA) recently awarded $23.9 million to US company Locus Biosciences, Inc. to continue development of a phage therapy against urinary tract infections caused by drug-resistant E. coli. Meanwhile, Tulane University’s Wimley Lab is developing potent antimicrobial peptides as alternatives to traditional antibiotics. These peptides attack bacterial membranes without requiring specific binding structures, making development of resistance much more difficult. Furthermore, different therapies are contemplated being used in combinations that will hit pathogens through multiple mechanisms, greatly decreasing the chance of their survival and pushing back any ability to development longer-term resistance.
Economic Challenges in Antibiotic Development
Despite significant progress in development of new antimicrobial treatments, bringing a therapy through trials and to patients faces significant challenges due to economic and systemic hurdles. The antibiotic business model is considered broken, primarily because the costs of development are not matched by the financial returns. Governments and organizations are beginning to recognize the gravity of antimicrobial resistance, which could cause 10 million deaths annually by 2050, and are exploring alternative funding models and incentives to stimulate antibiotic research and development. Despite initiatives like GARDP and CARB-X, which aim to accelerate the development of new antibiotics, the current efforts have been deemed insufficient by experts and the World Health Organization. Most new drugs are simply derivatives of existing classes. This means they arrive on the scene with limited efficacy against resistant strains, and so the global antibiotic pipeline remains underfilled of truly novel and effective solutions. The economic reality is stark: it costs up to $1.5 billion to develop a new antibiotic, but the median sales in the U.S. are only about $16.2 million. This discrepancy highlights the need for a restructured economic approach that not only fosters innovation but also makes the antibiotic market viable and attractive for pharmaceutical companies. A new initiative laid out in the UK hopes to tackle this by introduction of a subscription model and 5-year plan to fund the development of new antimicrobials while slowing further development of resistance. This model would pay pharmaceutical companies a fixed annual fee based on the value of the antimicrobials to the NHS, rather than the volume sold, reducing the incentive for overuse. Meanwhile, in 2023, a group of U.S. Senators and Representatives from both parties reintroduced the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act in order to drive development of novel antimicrobials and antibiotics. However, enough bipartisan agreement has not been fully reached for the act to pass and become mandate.
Fostering Global Cooperation to Combat AMR
Overall, stopping the spread of AMR will require a coordinated global effort between governments, clinicians and the biotech industry. Some of the key strategies include the 1) implementation of robust antimicrobial stewardship programs to ensure the rational use of antibiotics and 2) development of truly novel antimicrobials and rapid diagnostics. The One Health approach, aimed at addressing the interconnectedness of human, animal, and environmental health, will be crucial for managing AMR by reducing inappropriate antimicrobial use across all sectors and improving areas adjacent to treatment itself such as hygiene, infection control, and waste management. The development of enhanced surveillance systems is necessary to begin to monitor antibiotic use and resistance patterns, as this information will inform both public policy decisions and regulatory actions. Additionally, accessible public education and awareness campaigns will be help promote a more responsible antibiotic use and prevent infections. A concerted effort from governments, healthcare providers, researchers, and other stakeholders is critical to mitigate the global health crisis posed by AMR and to prevent a return to a pre-antibiotic era that is now dominated not by more mundane infections, but by true super-bugs capable of causing a wave of global pandemics.
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The Tulane Medicine team, who is also the Tulane Digest Team, is partnering at BIO 2024 this week. You can send a request through the BIO partnering system, or email us directly to arrange a time to connect.
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Recent Podcast Episode Drops:
Whether for travel entertainment or a quick listen between meetings, check out 6 recently released bite-size episodes of BIO from the BAYOU. Check them out on the BftB Website, Apple Podcasts, Spotify, or anywhere you podcast.
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Curated Research and Research-Related News Summaries, Analyses, and Syntheses. Published on behalf of The Tulane University School of Medicine. Content is generated by reviewing scientific papers and preprints, reputable media articles, and scientific news outlets. We aim to communicate the most current and relevant scientific, clinical, and public health information to the Tulane community – which, in keeping with Tulane’s motto, “Not for Oneself but for One’s Own”, is shared with the entire world.
Alexis L. Ducote, PhD: Editor-in-Chief
Special thanks to James Zanewicz, JD, LLM, RTTP and Elaine Hamm, PhD for copy-editing assistance.