Over the past 90 years, antibacterial discovery has gone from boom to bust.
For about 30 years in the middle of the 20th century, pharmaceutical companies regularly churned out new classes of the drugs, many of which doctors still use today, such as penicillin and the tetracyclines. However, by the 1980’s, discovery slowed and companies started leaving the field, drawn by the rise of profitable drugs in other therapeutic areas. As a result, only one successful new class of antibacterial drugs has been discovered since the late 1980’s (bedaquiline). This is the story of antibiotic resistance, or the Rise and Fall of Antibiotics. With growing numbers of bacterial strains resistant to existing drugs, pharmaceutical experts have been at a loss to know what to do. The success of early antibiotics saved many lives. It was reported in 1951 for example, thanks to drug treatment, the pneumonia mortality rate dropped by 50% in the previous decade. The antibacterial development boom started after the discovery in 1943 of streptomycin, the first antibiotic to treat tuberculosis.
Albert Schatz and his supervisor Selman A. Waksman, found the compound in Streptomyces bacteria. Streptomyces lives in soil, and soon pharmaceutical companies in the U.S., Europe and Japan started screening soil microbes. These companies were tapping into a microbial war that had been going on for many centuries in the soil. In a typical screening program, company microbiologists would obtain soil samples from across the globe. When soil samples came in, the microbiologists would first isolate the many different microbes present and then grow them separately in liquid cultures. The resulting broths were tested to see whether they could stop the growth of a particular pathogen, such as Staphylococcus aureus or Escherichia coli. If they did, then the real work began of isolating the active molecule. From the 1940’s to the 1960’s, companies improved this method and discovered about 20 major antibacterial classes, including the tetracyclines, the macrolides and the glycopeptide vancomycin. As scientists studied the major classes, they found how the antibacterials worked. The ß-lactams, such as penicillin and cephalosporin, inhibited cell wall synthesis. Tetracyclines, macrolides, and aminoglycosides affect protein synthesis. and the quinolones disrupted DNA replication. Medicinal chemists played a significant role in the boom by developing antibiotics with improved properties. Beecham Research Laboratories, an English Company that became part of GSK, produced several important derivatives of penicillin. An example was methicillin, developed in 1959, had a 2,6-dimethoxyphenyl side chain which shielded the compound from some some ß-lactamases, the enzymes that enable bacteria to resist penicillin. Discoveries of new classes started to taper off during the 1970’s. Companies started to see diminishing returns from their screening programmes. In the 1950’s, companies had to screen through around 1000 bacterial cultures to find a compound no one had seen before. To find Daptomycin, which was discovered in 1987, and is one of the last new classes to reach the market, scientists had to pick through about 10 million cultures. The rise and fall of antibiotics was upon us. In the late 1990’s, the industry tried to improve antibacterial discovery by turning to genomics. When the genome of Haemophilus influenzae was publicized in 1995, companies such as GSPK thought they could find new drugs by searching for genes essential for bacterial survival in multiple species. Then by using in vitro assays, they screened for compounds that inhibit the activity of associated proteins. The strategy failed for multiple reasons.
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