On Molds and Accidental Discoveries: The Birth of Antibiotics

"I stumbled upon something unexpected. When I woke up on that September morning in 1928, I certainly didn't plan to transform medicine by discovering the first antibiotic. Yet, that's precisely what happened." — Alexander Fleming on the discovery of penicillin

In September 1928, microbiologist Alexander Fleming returned to his London lab to find mold contaminating his bacterial cultures—an unwelcome sight for any scientist.

Typically, a contaminated experiment is deemed a failure, but Fleming observed that the mold appeared to inhibit bacterial growth, suggesting it produced a substance harmful to the bacteria. This marked the discovery of penicillin, the first antibiotic.

Although Fleming recognized the significance of his finding, it went largely unnoticed by the scientific community until the late 1930s, when an Oxford team developed an effective purification method for penicillin. This sparked the antibiotic revolution.

Antibiotics and Resistance

Sadly, antibiotics are not a permanent solution. As bacteria evolve alongside us, they develop resistance to the medications we use against them.

What does this entail? Unlike viruses, which consist of a simple structure with genetic material, bacteria are complex, single-celled organisms.

Bacterial cells share similarities and differences with animal cells. Consequently, when bacteria infect a host, we can combat them with antibiotics that target specific bacterial structures. The side effects of antibiotics stem not from harming our cells, but from disrupting the beneficial bacteria that coexist with us.

Bacteria reproduce by replicating their DNA and dividing, leading to rapid population growth under optimal conditions. As they multiply, random mutations can occur, and these mutations can be inherited by offspring.

If a mutation is detrimental, the bacteria are unlikely to survive and pass it on. Conversely, beneficial mutations can enhance survival and reproduction, especially if they confer resistance to an antibiotic, which then selects for those resistant strains.

The Threat of a Pre-Antibiotic World

Antibiotic resistance is not a distant threat; it is a reality we face today. Resistance to antifungal agents is also on the rise. Multi-drug resistant bacteria, often referred to as 'superbugs,' are already common, including well-known pathogens like Staphylococcus aureus.

The frequency of resistant strains has surged in recent decades. For instance, the antibiotic ceftaroline was introduced in 2010, yet a resistant strain of Staphylococcus was identified just a year later.

The WHO estimates that, if current trends continue, antibiotic resistance could lead to approximately 10 million deaths annually by 2050—compared to around 3 million deaths attributed to Covid-19 in 2020.

While bacteria may spread at a slower rate than viruses, current healthcare infrastructures may not be equipped to handle a surge of resistant infections. A return to a pre-antibiotic era would complicate treatment for even minor infections and would make routine medical procedures, like surgeries, significantly riskier.

The emergence of resistance is closely linked to the misuse of antibiotics, including inappropriate prescriptions and excessive agricultural use. What steps can we take to combat this issue?

On the Development of New Antibiotics

It may come as a surprise, but the rate of new antibiotic introductions has actually declined since the 1990s. This is largely due to the reliance on private companies for the development and production of drugs, which has proven unprofitable for antibiotics. These medications are typically used for short durations and tend to work quickly, making them less lucrative compared to treatments for chronic conditions.

A cost-benefit analysis conducted in 2013 revealed that the net present value of a new antibiotic is approximately $50 million, in stark contrast to around $1 billion for a drug targeting neuromuscular diseases.

Moreover, introducing new antibiotics is not a guaranteed solution, as bacteria will inevitably develop resistance again. However, judicious use of existing antibiotics can help delay this process, allowing time for the development of new treatments.

Fighting Bacteria with a 'Collateral' Strategy

Recent research in Nature Communications by a Spanish team suggests using a phenomenon known as collateral sensitivity (CS) to combat bacteria without relying on new antibiotics.

CS refers to the observation that bacteria resistant to one antibiotic may become more vulnerable to another. While it might seem that utilizing this approach would simply lead to the emergence of a new resistant strain, the situation is more nuanced.

Scientists have gained insights into the molecular mechanisms behind certain antibiotic resistances. They propose employing this understanding to temporarily induce resistance in bacteria, thereby utilizing the accompanying CS to apply a second antibiotic without fostering the development of resistance.

In their study, the researchers focused on the multi-resistant bacterium Pseudomonas aeruginosa, which can be opportunistic in nature. They demonstrated that strains resistant to ciprofloxacin (antibiotic A) exhibited collateral sensitivity to tobramycin (antibiotic B).

The resistance to antibiotic A is attributed to a mutation that increases the production of a membrane channel, which expels antibiotic A from the bacterium. By transiently inducing this overproduction, the researchers aimed to create a state of resistance to A, thus increasing susceptibility to B.

Through a series of well-designed experiments, the team established that CS can be artificially and temporarily induced, effectively eradicating various strains in controlled settings. Importantly, once the induced CS is reversed, surviving bacteria do not display heightened resistance to either antibiotic A, B, or other antibiotics.

Although these findings require further clinical application, they offer a promising new avenue in the battle against bacterial resistance.

We Must Do Better

Scientific and technological advancements have afforded our society a level of comfort that we often take for granted. Just as socio-political systems demand vigilance and scrutiny, so too should our interactions with the natural world and its organisms, including microbes.

The Covid-19 pandemic served as a stark reminder of how fragile our systems can be. Rapid changes in dynamics can occur, underscoring the importance of proactive planning and long-term strategies to mitigate foreseeable crises.

The issue of antimicrobial resistance, much like climate change, has been discussed for years. Yet, the pace of new antibiotic production appears to be slowing, and the market for these crucial medications is deemed "broken" and unprofitable. This raises important questions about whether healthcare responses to emergencies should rely more on public long-term planning and funding rather than solely on private enterprise.

Our intuition often fails to recognize the dangers posed by non-linear phenomena, such as disease outbreaks and climate shifts, only becoming apparent when it may be too late to respond. The lessons from Covid-19 and climate change emphasize the need for proactive measures—let's heed these lessons.