History of Antibiotic Development
Antibiotics are microbial products that have killing or inhibiting effects on some specific microorganisms (bacteria, fungi, rickettsia, viruses, mycoplasma, etc.) at high dilution. The first antibiotic, salvarsan, was introduced in 1910. In just over 100 years, antibiotics have revolutionized modern medicine and extended the average human life expectancy by 23 years. The discovery of penicillin in 1928 opened the golden age of natural product antibiotic discovery, reaching its peak in the mid-1950s, since then, the discovery and development of antibiotics has gradually declined, and the resistance of many human pathogens has evolved, leading to the current antibiotic resistance crisis. This article provides an overview of the history of antibiotic discovery, the major classes of antibiotics, and their future development.
Antibiotic classes, their clinical introduction, and resistance identification. (Spagnolo F., 2021)
Discovery and development of antibiotics
Penicillin observed by Alexander Fleming in a contaminated petri dish in 1928. Later, Norman Heatley, Howard Florey, Ernst Chayne, and colleagues at Oxford University purified penicillin, and by 1940 had produced a product pure enough to be injected into the human body. In the first clinical trial, although the amount of penicillin was very small, the effect was very impressive. It was this miraculous antibiotic that saved thousands of lives threatened with death during the Second World War. Penicillin became the first antibiotic to be used clinically as a therapeutic drug.
After the discovery of penicillin in 1928, the golden age of finding new antibiotics really began in the 1940s. Microbiologist Selman Waksman discovered streptomycin in 1943 by systematically testing the ability of soil microbes (primarily Streptomyces) to use bacteria to produce antibiotics, becoming the first antibiotic used to treat tuberculosis. The method used by Waksman was widely adopted by the pharmaceutical industry, and over the next 20 years there were discoveries of chloromycin (1947), chloramphenicol (1948), oxytetracycline (1950), nystin (1950), erythromycin (1952), kanamycin (1958), and more. The intergeneration of these antibiotics enabled the successful treatment of bacterial diseases and rickettsial disease at that time, and significantly extended human life expectancy.
After entering the 1960s, people's search for new antibiotics from microorganisms slowed down significantly, replaced by the emergence of semi-synthetic antibiotics. In 1958, N.C.Sheehan synthesized 6-aminopicillanic acid, thus opening the way to the production of semi-synthetic penicillin. In 1961, Abraham discovered cephalosporin C from a metabolite of cephalosporus. After decades of development, cephalosporins have emerged in the first, second, third and fourth generations.
Types of antibiotics
Initially discovered antibiotics, mainly have the effect of killing bacteria. However, with the development of antibiotics, many different types of antibiotics have gradually appeared in clinical practice. Antibiotics include imitation products synthesized by chemical methods, microbial products with anti-tumor, anti-parasitic and other effects, and semi-synthetic derivatives of antibiotics. It can be divided into β-lactam antibiotic, aminoglycoside class, tetracycline class, macrolide class, chloramphenicol class, lincomycin class and peptide class antibiotics, as well as anti-tuberculosis, antifungal agent and so on.
Antibiotics at BOC Sciences
Antibiotic production services at BOC Sciences
Future development of antibiotic
With the wide application of antibiotics, the clinical resistance of bacteria to commonly used antibiotics is increasing, and the emergence of antibiotic resistance reduces the efficacy of antibiotics. Therefore, human beings need to constantly develop new drugs. New antibiotics based on different mechanisms are at different stages of development. In addition, the development of antibody drugs and antibacterial peptide drugs has also become a new force in the field of antibiotic research and development. The research and development of these new antibiotics is expected to solve the clinical antibiotic resistance, but also provide a new way for the prevention and treatment of pathogenic microorganisms.
Small molecule antibiotic
Current small molecule antibiotics are mainly derived from microbial natural products, but it is difficult to identify new compounds from this resource. Actinomycetes have always been the main source of antibiotics, and now new antibiotics can be discovered by exploring other species of bacteria. For example, Lewis has identified two antibiotics with novel modes of action, teixobactin, derived from the β-Proteus bacterium (Eleftheria terrae sp.) isolated from soil samples using isolation chips (iCHIP), and darobactin, which has been isolated from soil samples. It is a novel ribosomal peptide (RiPP) discovered in 2019 from the metabolites of Luminobacter elegans.
Many bacteria in the environment, such as actinomycetes, possess genetic programs to produce 20 to 40 natural products, while fungi can contain many more. Using modern genomics, genome mining, synthetic biology, and analytical chemistry can help us discover new antibiotics in these natural products. These antibiotics have a novel mode of action: they inhibit cell division by blocking the activity of autolysins necessary for daughter cell separation. Another source of new antibiotics is synthetic molecules. The Myers Laboratory has established highly innovative modular synthetic pathways for the generation of novel tetracycline, macrolide, and lincosamide antibiotics, greatly expanding the diversity of these compound classes beyond the limits of natural biosynthesis.
Peptide chain antibiotics
With the increase in AMR, there has been renewed interest in exploring antimicrobial peptides (AMPs). Although there are a few approved peptide antibiotics (bacitracin, gramomycin, polymyxin, and dattomycin), most are hemolytic or renal toxic, limiting their use. Coupled with high synthetic costs and sensitivity to protease inactivation, few peptide-based therapies have completed clinical trials. This problem has plagued polymyxin, the last-line treatment for drug-resistant gram-negative infections. To avoid safety concerns, the researchers designed a polymyxin analogue, MRX-8, that is both effective and safe. MRX-8 is currently undergoing Phase I clinical trials in China and the United States.
Combination therapy with antibiotics
Adjuvants or combinations of antibiotics can help overcome resistance. For example, a combination of bedaquinoline, primani, and linezolid was recently approved for the treatment of extensively drug-resistant mycobacterium tuberculosis. Since the likelihood of developing resistance to two drugs is less than the likelihood of developing resistance to one, combining antibiotics may hold promise for reducing antibiotic resistance.
Bacteriophage treats resistant infections
Phages are increasingly attractive for treating highly resistant infections. These bacterial viruses were discovered in the early 20th century and were quickly used to control infections. However, early efforts have been hampered by a lack of understanding of the phage's host range, manufacturing and storage methods. In recent years, the effectiveness and narrow spectrum of phages have been increasingly recognized as a "potential stock." Since the first commercial phage products were launched in 2006, species-specific phages have been widely used in the agriculture and food industry to control dangerous foodborne pathogens such as Listeria monocytogenes, Salmonella, and Shigella.
Probiotic strategy treats resistant infections
The use of broad-spectrum antibiotics disrupts the gut microbiota, allowing pathogens such as Clostridium difficile to survive there. In order to restore a healthy gut microbiome, people try to replace, supplement, or edit the gut microbiome. The most significant change to the gut was fecal microbiome transplantation from a healthy donor, a strategy that, while successful in reducing C. difficile, was also prone to death by accidentally infecting pathogens in complex fecal microbiome samples. To reduce this risk, researchers are working to supplement the gut microbiota with more well-defined probiotics, and it remains to be seen how effective these probiotics will be. Future strategies may use engineered strains to make precise edits of the gut microbiome, specifically to eliminate or prevent colonization of pathogens.
Vaccines address antibiotic resistance
Infection prevention is a more effective strategy in infection control. Therefore, developing vaccines to treat common bacterial infections is a reliable way to address the antibiotic resistance crisis. Unlike antibiotics, vaccines are not susceptible to resistance, and they can prevent the spread of antibiotic resistance by preventing infection. For example, the rate of pneumococcal infection associated with antibiotic resistance in infants and the elderly declined with the use of a polysaccharide conjugate vaccine against 13 serotypes. There are dozens of vaccine candidates targeting pathogenic bacteria in various stages of clinical trials.
References
- Hutchings, M. I., et al. Antibiotics: past, present and future. Current Opinion in Microbiology. 2019, 51: 72-80.
- Miller, M. J., Liu, R. Design and syntheses of new antibiotics inspired by nature's quest for iron in an oxidative climate. Accounts of Chemical Research. 2021, 54(7): 1646-1661.
