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ANTIBIOTICS From Bacterial and Fungal Cells to Healthcare A Brief History of Antibiotics • 1928 Alexander Fleming isolated penicillin from a mould Penicillium notatum. • 1930 First record of penicillin being used to cure a disease. A crude extract was used to clear an eye infection in a three-year old boy. • 1939 Ernst Chain & Howard Florey started to isolate and purify penicillin, which was essential to help combat infections during World War II. • 1944 Selman Waksman and colleagues isolated streptomycin from a soil bacterium Streptomyces griseus. Streptomyces bacteria have been the source of almost two-thirds of all known natural antibiotics and the majority of new antibiotics for the past 50 years, including the tetracyclines and erythromycin. • 1945 Fleming, Chain & Florey share the Nobel Prize. • Today, UK scientists are sequencing the genome of Streptomyces coelicolor, which may lead to new approaches to the production of antibiotics. Sequencing one species in detail will provide valuable information that can be applied to many other species. What is an antibiotic? An antibiotic is a substance produced by a living thing that is capable of destroying or inhibiting the growth of another living thing. Generally antibiotics are produced by bacteria or fungi, although they can come from plants, insects, amphibians or even mammals. Chemists can alter the structure of a naturally produced substance to make it a more effective antibiotic. Antibiotics like the cephalosporins and the penicillins are extremely valuable to industry. bbsrc biotechnology and biological sciences research council How do antibiotics work? Antibiotics may be used to treat bacterial disease by preventing the formation of bacterial cell walls. Some antibiotics like penicillin and cephalosporin inhibit the synthesis of peptide links between peptidoglycan molecules in bacterial cell walls. This causes the cell wall to become weak and the bacterium to explode.These peptidoglycans are not found in mammalian cells, which is why the antibiotics are selectively toxic towards bacteria. Some antibiotics interfere with DNA replication. Rifampicin binds to RNA polymerase in bacteria and prevents transcription.The anthracyclines interfere with DNA synthesis in all organisms, but the effect is most marked in rapidly growing cancer cells. Some antibiotics interfere with protein synthesis. Antibiotics like streptomycin and tetracycline interfere with protein synthesis often by binding to the ribosomes. Some antibiotics can only bind to ribosomes from bacteria, but some like tetracycline can bind to ribosomes in mammals and bacteria. They are not harmful to humans because they are excluded from mammalian cells. Some antibiotics also promote the synthesis of abnormal proteins. Some antibiotics prevent cell membrane function. Most of the new peptide antibiotics work by binding to molecules (usually sterols) in the cell wall. This distorts the lipid bilayer and opens channels in the membrane that causes the cell contents to leak out. Bacteriostatic antibiotics prevent growth and multiplication, which gives the body’s immune system a better chance of fighting a bacterial infection. Bactericidal antibiotics kill their target bacteria. Bacterial resistance Bacterial infection is a serious health problem. So called “superbugs” are antibiotic-tolerant bacteria that cause health problems, especially in Intensive Care Units where the most vulnerable are treated. In some countries superbugs are endemic and some diseases are re-emerging as a threat in the UK. Superbugs can evolve resistance either by altering the target, by defusing the antibiotic or by preventing its uptake. Bacteria can become resistant by mutations in their own genes or by receiving genetic information from elsewhere. How can the scientists overcome resistance to antibiotics? • One way of tackling the problem of bacteria becoming resistant to antibiotics is to redesign the antibiotics. However the bacteria can also redesign their resistance. • Another approach is to create new antibiotics by mixing and matching the ingredients of existing ones. • Research at the University of Cambridge is looking at the pathway of enzymes that make chemicals, that include the antibiotic erythromycin. Changing this pathway may produce new antibiotics. • Research at the Institute for Animal Health has shown that bacteriophages (viruses that attack and destroy bacteria) can control bacterial infections in different tissues in animals.This suggests that bacteriophage treatment could be effective in treating and possibly preventing bacterial diseases in humans. • Many drugs work by binding to a specific site on a protein and altering its function. By using computer modelling, scientists can model this binding site and design drugs to fit it more snugly so that they are more effective. The tuberculosis story Historically, many people have been victims of turberculosis including Jane Austen and Henry VIII, this disease is still a problem today. Multi-drug resistant tuberculosis is found in many parts of the world and is now a concern in the UK. By 1995, one in seven cases of tuberculosis was resistant to all known antibiotics. In 2001, young people in London were warned about the risks of catching tuberculosis in clubs and bars. Scientists such as Dr Jim Naismith from the University of St Andrews are looking at new targets for treatment of tuberculosis. He is trying to find a new class of antibiotics by studying the structure of enzymes in the bacteria that might be targets. The structure of an enzyme found in Some antibiotics can only work when Mycobacterium tuberculosis bacteria are in their growing state. Scientists have discovered a natural chemical that can change the bacteria from their dormant state to their growing state making them more susceptible to antibiotics, which may have implications for treating tuberculosis. How can we help prevent resistance 1. Patients should take the full course of antibiotics to kill ALL of the bacteria. In reality patients stop taking their medication when they feel better, allowing some partially-resistant bacteria to survive and spread. 2. By regulating the use of antibiotics in animal feeds and medicine. In Europe the antibiotics that are used for animal feeds are not used in medicines for humans. 3. By selling antibiotics only with a prescription, which will ensure that a full course of antibiotics is given to the patient and by advising on the proper usage at the pharmacy and health centre. For more information visit our exhibitions website at www.bbsrc.ac.uk/life