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Why is the development of new antibiotics so difficult?

Antibiotics are the ‘wonder drugs’1 that have contributed to the control of infectious diseases that were the leading causes of human morbidity and mortality for most of human existence2. They are chemicals that kill or inhibit the growth of microbes, especially bacteria; hence, they are used widely to treat infections3. Although human exposure to antibiotics has increased during the modern ‘antibiotic era’, research has shown that humans have been exposed to antibiotics as early as 350-550 CE; for example, traces of the antibiotic tetracycline have been found in human skeletal remains from ancient Sudanese Nubia during this time period. Exposure to antimicrobials in the pre-antibiotic era was speculated to have been derived from diet, antibiotic-producing microbes in soils, and potentially through remedies used in natural alternative medicine. However, many associate the beginning of the modern ‘antibiotic era’ with two physicians: Paul Ehrlich and Alexander Fleming. Ehrlich described antibiotics as a “magic bullet” that selectively targets only disease-causing microbes and not the host, an idea established on an observation that aniline and other synthetic dyes could stain specific microbes and not others, which eventually led him to begin a large-scale systematic screening programme. This systematic screening approach was utilised by pharmaceutical companies, significantly contributing to the discovery of other drugs, including antibiotics, the discovery of sulphonamides, for example. Fleming was widely acknowledged for his discovery of penicillin in 1929, credited for the discovery of the world’s first antibiotic, and was one of the first who cautioned about antibiotic resistance if used too little or for a short period of time during treatment2. 

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The period between 1950 to 1960 is known as the golden age of antibiotic discovery since approximately half of the drugs frequently used today were discovered during this period4. However, the increased use of antibiotics in both human and animal populations has led to the development of resistant bacterial pathogens. Thus, this overuse and misuse of these drugs has created a global health crisis5. Currently, the increase in the appearance of resistant strains establishes a need for novel antibiotics; however, few new antibiotics are under development, with the latest discovery of a new antibiotic class being over thirty years ago in 19876. Figure 1 illustrates that many novel agents were discovered during the golden age, whereas for the past few decades, there has been a ‘discovery void’ where no new classes have been discovered, this lack of antibiotic development in recent years is the main cause as to why trends indicate that resistant bacteria could lead to the deaths of 10 million a year by 20507, with treatable infections such as gonorrhoea possibly becoming untreatable8 without further intervention. The reasons for this decline despite an increase in global demands can be analysed both biologically, chemically, and economically.

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Figure 1 - timeline of the discovery of novel agents6. 

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A reason for the decline in the discovery of novel agents can be traced back to pharmaceutical companies and the investment required for antimicrobial discovery. A 2017 estimate indicates that the cost of developing an antibiotic is approximately 1.5 billion USD, requiring over 10 years of research and development, including screening, animal testing and clinical trial stages. Figure 3 illustrates the average time needed to produce a new antibiotic, and the time taken for each stage. Industry analysts estimate that the average revenue generated from an antibiotic is roughly 46 billion USD per year, thus, the profits do not justify the investment9. In addition, antibiotic prices are generally low because many countries have agencies that contribute to the price assessment rather than the manufacturers alone. For example, in the UK, the National Institute for Health Care Excellence assesses the clinical strength and cost-effectiveness of new medicines. With government agencies maintaining a lower price for antibiotics. Many other countries have similar programmes; thus, companies are not able to raise their prices to achieve higher profits worth the research and development investment. Due to antibiotic resistance leading to an increased need for novel agents that bacteria will not be resistant to, as well as the positive correlation between microbial resistance and the use of particular antibiotics, new antibiotics are not usually prescribed by physicians to help delay the development of bacterial resistance. As a result, novel antibiotics will be stored for emergency scenarios, decreasing sales and profits. For example, physicians store the antibiotic colistin as the last resort when infections are resistant to other treatment options10. Furthermore, when compounds are tested as potential antibiotics in the early stages of development, historical patterns reflect that only a small fraction of the compounds will make it to clinical development, which does not guarantee that the drug will work and eventually enter the market11, thus the failure rate is high.

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Figure 2 - a diagram showing the process of antibiotic development12

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Pharmaceuticals have spent billions trying to find new antibiotics, and failure to introduce the drug into the later stages of testing and the market has led to many pursuing the development of drugs in other areas, chronic illnesses, for instance13. Antibiotics are used for a short period of time, approximately 5 to 14 days before they are discontinued14, whereas drugs for chronic illnesses are used throughout a patient’s lifetime, so other drugs are more profitable and provide a greater return on investment. Therefore, many large pharmaceuticals are no longer willing to invest in the development of antibiotics, with only four still researching drugs in this field, so the likelihood of the discovery of novel agents is reduced. Smaller companies are currently attempting to replace large companies; however, many lack the experienced researchers large companies have. In order to correct this market failure, there should be more financial incentives for the development of antibiotics, while delinking research and development costs from drug pricing and the return that drug companies receive on investment15. For example, there could be financial rewards to the developer that are not based on the volume of use of the novel antibiotic. Collaboration between the public and private sectors may also prove to be useful.

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Furthermore, the discovery of new antibiotics is a scientific challenge. The chemicals which kill bacteria are prevalent; however, it is challenging to discover and develop chemicals which are not toxic to humans7, that enter and stay in the bacterial cell. Researchers look at high numbers of chemicals which can weaken or kill bacteria; the common methods include the inhibition of DNA synthesis, RNA synthesis, cell wall synthesis, or protein synthesis16. At present, there is still incomplete knowledge and understanding about methods of weakening bacteria, especially drug-resistant Gram-negative bacteria10. When coming into contact with violet-coloured dye, Gram-positive bacteria will stay coloured as their cell walls retain dye, whereas Gram-negative bacterial walls do not, since the external layer usually found in Gram-positive bacteria is partially replaced by an extra outer membrane17. The double membrane in Gram-negative bacteria repels antibiotics, as it is less permeable to chemical compounds. In addition, Gram-negative bacteria also contain an array of efflux pumps, expelling drugs out of the cell before they can harm the bacterium, illustrated in Figure 3. Thus, these factors make it challenging to design new antibiotics that target these types of bacteria. In order to search for more antibiotics against Gram-negative microorganisms, scientists need to increase their understanding of the bacterium’s defence mechanism to enable them to measure the extent to which a drug is able to stay inside the cell or cellular components11.

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Figure 3 - the limitations of antibiotic entry in Gram-negative bacteria in comparison to Gram-positive bacteria10

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Moreover, another challenge faced by researchers is the limitation of current chemical libraries. The success of antibacterial screening is dependent upon the quality of the chemicals assayed. The ‘golden age’ of antibacterial discovery involved the screening of natural products, observing products of fermentation and extracts of microorganisms that inhibit the growth of bacteria, without concerning their mechanism of inhibition. Pharmaceutical companies evaluated the costs of maintaining the resources for the research of natural products compared to the low probability of useful output, therefore deciding the chemical method, utilising libraries. However, current chemical libraries have limited chemical diversity, especially for the substances that may have the potential to target the factors preventing antibiotic entry in Gram-negative bacteria18. Therefore, without diverse antibacterial chemical libraries, this screening method would not lead to the discovery of new antibiotics19. 

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Additionally, there are also problems which prevent the discovery of novel antibiotics when researching natural products. The vast majority of antibiotic classes used clinically today have been isolated from soil, as natural products in soil microbes. However, most natural microbes from the environment are challenging to grow and culture in a laboratory, so in the past, only 1 percent of microbe species from soil could be grown by scientists. A study published in 201520 described a new method to culture microbes, allowing a group of scientists to grow 50% of microbe species in soil samples. Although this recent improvement could potentially lead to the discovery of new antimicrobial agents, half of the microbes unable to be cultured may produce products with antibiotic properties; therefore, current technology and culturing methods are still limiting the discovery of novel agents. Furthermore, the technology to explore other ecosystems which may contain useful microbes is limited. For example, marine organisms have not been studied well21, with scientists predicting that approximately 91 percent of ocean species are yet to be classified22. Therefore, the overwhelming majority of species have not been researched in detail. These species may have evolved to produce compounds that weaken or kill bacteria, so because current technology doesn’t support the discovery and research on organisms in other ecosystems, this could potentially limit exposure to new antibiotics.

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Despite the increasing need for novel antibiotics, there are various factors that prevent and decrease the rate of antibiotic production, including low incentives for pharmaceutical companies to invest in antibiotic development, the resistive nature of Gram-negative bacteria, the limited chemical library, and technological limitations. It can be argued that the factor most preventing antibiotic development in the short-term is a limited chemical library. This is because discovering new chemicals through exploration involves long-term commitment, but humans need an increase in new antibiotics promptly. With a more detailed and diverse chemical library, scientists are able to test only the compounds which they believe have the potential to become the next antibiotic. In order to make this library a success, scientists worldwide should share their knowledge and use bioinformatics to increase the number of compounds present in the library.

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Written by Natabhorn (Plume Plume) Kashemsri Na Ayudhaya

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References:

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