Solid-phase synthesis and anti-bacterial evaluation of cyclic lipopeptide antibiotics

SummaryOne of the principal threats to human health is infection by micro-organisms such as bacteria. Drug treatment is the first line of attack in order to kill the bacteria that are responsible for causing the infection. Drugs have been developed that work as a result of the differences between bacterial cells and human cells. By exploiting these differences, we can kill the bacterial cells and treat the infection without causing damage to the person that is infected. Unfortunately, there are a limited number of ways that we can target the differences between bacteria and humans and, so, there is a limit to the number of different types of antibiotic drugs that we can make. There is a lot of current research into new drugs that can kill bacterial cells in different ways.Over-use of antibiotics can cause bacteria to become resistant. Bacteria divide rapidly and the new bacterial cells that are produced are never exactly the same at the cells that they were produced from. Each time a bacterial cell copies itself, the copy is not perfect : there will be something very slightly different about the new cell. Sometimes these small differences that occur when the bacteria divide mean that they are no longer killed by an antibiotic: the small difference affects the part of the bacterial cell where the antibiotic works. So if someone with an infection is treated with an antibiotic, the antibiotic will kill nearly all of the bacteria, but there may be some left over that are not affected by the antibiotic. These survivors can then begin to divide and divide until there is a new infection, but this time, the bacteria are resistant to the antibiotic. Most of the antibiotics that we use have been around for a very long time, so there are some bacteria that are resistant to nearly all of them. The most well known of the resistant bacteria that is responsible for many deaths each year from infections acquired in hospitals is MRSA.One of the best sources of well-known and new drugs is nature. Many antibiotic drugs were first isolated from fungi (e.g. penicillin) or from other bacteria. Bacteria often produce antibiotics as a self-defence mechanism to kill other bacteria. One such new antibiotic that has recently been licensed for use is daptomycin. Daptomycin kills bacteria in a new way; it interferes will the bacterial cell wall causing the contents of the bacteria to leak out. Since daptomycin works in a new way, it can kill bacteria that are resistant to all other antibiotics. Finding antibiotics that work in new ways is very important as it allows us to treat resistant infections that may otherwise be life-threatening.Daptomycin is made up from a ring of amino acids (the building blocks that make up proteins) to which a small fat is attached. Rather than extract and produce daptomycin from bacteria, this research project will develop a method to produce it synthetically. We will build-up the structure attached to small plastic beads using these amino acids in a stepwise manner. Once the molecule is finished, it will be removed from the bead and purified. We will use the same method to make small changes to the structure of the antibiotic to see which parts of the drug molecule are important for its activity as an antibiotic. We will also use the methods developed to synthesise other, similar antibiotics that are produced by other bacteria, to see if they have similar activity. There are many different kinds of antibiotics very similar to daptomycin that may be very useful drugs, but they have yet to be studied in any detail. All of the antibiotics that we produce will be tested for their ability to kill bacteria, including MRSA.This research project will give us a new method of making these antibiotics and will help us to understand how they work. It will also allow us to develop new antibiotics that may eventually be useful as drugs to treat life-threatening infections in patients.