**2.2. Foundation of the antibiotic era**

Bacteria were first identified in the 1670s by van Leeuwenhoek, following his invention of the microscope. The relationship between bacteria and diseases gradually set up in the nine‐ teenth century. Since then, researchers started to try and find effective antibacterial agents.

Paul Ehrlich is the father of chemotherapy and was honored with the Nobel prize due to the molecular side-chain theory of immunity. His concept of "magic bullet" is that the chemicals selectively target only disease-causing microbes but not the host cells. In 1906, Ehrlich, together with Bertheim, developed hundreds of derivatives of Atoxyl, and final‐ ly discovered compound 606, a gold powder [9; 11]. In 1909, he found that Compound 606 could cure syphilis-infected rabbits in experiments; it could also improve terminal patients with dementia and cured early stage patients with infected sores [11]. It was publicly released as salvarsan in 1910. Despite the adverse side effects, salvarsan and it's derivative neosalvarsan kept the status of the most frequently prescribed drug until the introduction of penicillin in the 1940s [12]. Amazingly, the chemical structure of salvar‐ san hadn't been known until 2005 [13].

The systematic screening approach introduced by Paul Ehrlich became the cornerstone of drug search strategies in the pharmaceutical industry. Sulfonamidochrysoidine (also named prontosil), the first commercially available antibiotic, was first synthesized by Bayer chem‐ ists Josef Klarer and Fritz Mietzsch in 1930s by this approach. Then Gerhard Domagk found its effect against Streptococcus pyogenes in mice [14]. Four years later he received the Noble Prize. Eventually prontosil was recognized as a precursor for a new class of antibacterial agents— sulfonamides.

The effect of mould on bacterial colonies hadn't been investigated until 19th century, al‐ though the antibacterial properties of mold had been known since ancient times. In 1921, Alexander Fleming observed some substances called lyzosomes which could dissolve bacte‐ ria. In 1928, he discovered that a specific mould species inhibited the development of Staph‐ ylococcus bacteria. The species was known as Pencilliumnotatum and the filtrate was called penicillin [15]. In 1940, Howard Florey and Ernst Chain worked out how to purify penicillin for clinical testing [16]. All the three researchers were awarded the Nobel Prize in 1945, and since then the era of antibiotics had been initiated. Penicillin became the top therapeutic molecule because of its widespread use and the magnitude of the therapeutic outcomes, and also because of the technologies developed for production of penicillin which became the basis for production of all subsequent antibiotics and other bioproducts in use today [17].
