The end of an Antibiotic era?

Anjan Venkatesh explains the potential crisis facing the world of medicine as bacteria become increasingly resistant to antibiotics.

Few anecdotes are as enduring in the world of science as the story of how Alexander Fleming discovered the first modern antibiotic, penicillin. On 3rd September 1928, Fleming, a Scottish microbiologist, returned to his lab after a month’s holiday. He noticed that an uncovered plate of Staphylococcus bacteria on his lab bench had mould growing on it. Curiously, bacteria had grown all over the plate, except around the mould. This antibacterial effect of the Penicillium mould had been documented before, and Fleming’s research did not garner much attention until it was picked up by American researchers at the start of the Second World War. But yet, in the public consciousness, this ring of inhibition heralded one of the most groundbreaking scientific discoveries of all time. Antibiotics, along with vaccines and improved hygiene, revolutionized medicine. Diseases could be treated and outbreaks quelled before they became epidemics.

Following his discovery, Fleming methodically grew Penicillium mould, produced the antibiotic (which he nicknamed “mould juice”), and tested it on bacterial cells. He found that using too little antibiotic or stopping the doses too early caused the cells to become resistant- they were no longer killed off by the same amount of penicillin. Over time, they would become immune to the effects of penicillin entirely. How could this happen? Different classes of antibiotics disrupt different processes in the bacterial cell, including cell wall synthesis and DNA synthesis. Bacteria can survive this onslaught on their cellular machinery by three main mechanisms- changing membrane permeability to the antibiotic (not letting it into the cell), degradation (breaking down the antibiotic), and by changing the protein targeted by the antibiotic to render it untargetable. 

Once an antibiotic is in use for treating infections, the emergence of a resistant strain is an inevitability. A 2015 report found that resistant strains are typically reported within three years of the introduction of a new antibiotic. So far, strategies to treat resistant outbreaks have relied on reserving some antibiotics (to which resistance is less common) for the second and third tiers of treatment. Some, like carbapenems, are reserved as the final line of treatment when all other antibiotics have failed. This has happened numerous times in the past, with multi-drug resistant tuberculosis and Staphylococcus aureus (MRSA) outbreaks regularly featuring in the news. Some cases of bacterial infections that are resistant to all known antibiotics have also been reported. 

Dr Keiji Fukuda, former assistant director-general at the World Health Organization, wrote in a 2014 report: "Without urgent, coordinated action by many stakeholders, the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill." Given the urgency of the problem and the massive potential for epidemics and loss of life, the onus is on governments to fund research and develop policy aiming to mitigate resistance. The WHO’s 2015 publication “Global Action Plan on Antibiotic Resistance” lays out the main strategies to meet this end goal. Over the past decade, many governments (including that of Ireland) have published their own action plans. 

Any plan to combat resistance involves spreading awareness about antibiotic misuse and curbing unnecessary prescriptions. Antibiotics are often wrongly prescribed to patients with viral infections, and prescriptions are not adequately monitored. Many bacterial infections in humans are caused by “opportunistic” bacteria (like Streptococcus) that can harmlessly live in the human body until the immune system is weakened, at which point they cause an infection. If these bacteria acquire resistance through repeated exposure to antibiotics, an infection is far more dangerous. The problem does not end here- when antibiotics are excreted out of the human body, they find their way into sewage, and often into the environment. Even though they are far less concentrated at this point than when they are in the body, over time they contribute to the emergence of resistant bacteria in the environment. 

In the absence of clear, accessible, and accurate information about healthcare and disease, misinformation and paranoia thrive. For example, the plethora of misinformation about vaccines has led many parents to refrain from vaccinating their children.This includes vaccines against bacterial infections such as Streptococcus and tuberculosis, creating a fertile environment for resistant bacteria to spread. As a result, outbreaks of preventable diseases are occurring in developed countries for the first time in decades. In the 20th century, vaccines and antibiotics reduced infectious disease mortality and child mortality rates to unprecedented lows. We do not need to look very far into the past to see what the world looked like without them. 

Spreading awareness and regulating antibiotic misuse can help stave off antibiotic resistance, but they cannot completely stop its spread. Bacteria will continue to evolve resistance to any new antibiotics that are introduced. The only real cure is to introduce new drugs at a faster rate or to develop drugs that bacteria are less likely to become resistant to.  

A key challenge in developing any new antibiotic drug is specificity- how do you target only the cells that you want to kill? Bacterial cells are different from human cells in many important ways. For example, they have cell walls, while human cells don’t. Many of the most commonly used antibiotics affect the ability of bacterial cells to build the cell wall, while causing no harm to human cells. Now, however, we are running out of obvious differences to exploit. One strategy is to target bacteria-specific proteins that human cells do not have. Identifying such “druggable” proteins that can be targeted without affecting human cells is an extremely laborious, expensive process. 

As a result, antibiotic discovery has slowed considerably since the mid-20th century. As of September 2019, only 13 antibiotics were in the final stage of clinical trials. Most new antibiotics are slightly modified versions (or combinations) of existing drugs. The cost of screening thousands of different compounds to find few (and often zero) viable antibiotics is astronomical. The rewards are often modest, with limited drug viability and rapid emergence of resistance. From the perspective of a pharma company trying to turn a profit, there are better ways to spend money. Pfizer, for example, shut down its main antibiotic drug discovery program in 2011 citing lack of shareholder returns. 

Some other promising alternatives are being explored- the “Ancientbiotics” group in University of Nottingham have found some traditional plant-based medicines to be effective in treating resistant infections. There has also been a recent resurgence of interest in bacteriophage therapy to overcome antibiotic resistance. Bacteriophages, or phages, are viruses that infect bacteria, produce copies of themselves, and eventually destroy the bacterial cell. Bacteria can become resistant to phages, but through the same mechanisms, phages can (and do) evolve to overcome this resistance. This makes them especially appealing. Phages are also highly specialized to the bacteria that they infect, and are incapable of entering human cells. However, because phages are so specialized, the exact species of bacteria causing the infection must be determined before treatment can be started- which is not always feasible. As of now, reliable alternatives to antibiotics are few and far between.