Studies on Enzyme Mechanism and Antibiotic Resistance Strategies

点击翻译按钮获取中文摘要

The emergence of resistant strains of bacteria presents an ever-increasing problem to human health. The ability of bacteria to rapidly mutate and develop defense mechanisms against clinically used antibiotics means that we will soon run out of effective drugs to combat bacterial infections. This proposal describes three projects that will help us to understand and possibly control the bacterial defense mechanisms that allow them to survive in a human host. The first project involves an enzyme that produces a compound called staphyloxanthin that helps the pathogenic bacteria Staphylococcus aureus survive in the human body. Our proposal describes studies that will uncover how the enzyme constructs this molecule. Such knowledge can be used to prepare molecules that will prevent the enzyme from doing its job, and thereby depriving the bacteria of their defense mechanism. Such molecules could then be used as antibiotics. The second and third projects revolve around resistance mechanisms that bacteria use to evade clinically used antibiotics. In the second project we are targeting a protein called AmpG that plays a key role in resistance to the beta-lactam antibiotics, such as penicillin. When AmpG is functional it helps to "sense" the presence of the antibiotic and leads the bacteria to produce an enzyme called a beta-lactamase that then destroys the antibiotic. This renders the antibiotic ineffective and allows the infection to spread. We plan to study the way AmpG operates and discover which molecules are most effective at getting it to signal beta-lactamase production. Interfering with AmpG function could allow the beta-lactam antibiotics to function effectively once again. In the third project, we study an enzyme called ArnD that is involved in the resistance of certain pathogenic strains of bacteria against antibiotic peptides such as polymyxin. This enzyme helps to coat the surface of the bacteria with molecules that prevent the antibiotic from binding and killing the bacteria. We plan to demonstrate the activity of ArnD for the first time and to study how it generates the "coating" compounds. This may ultimately lead to the production of inhibitors of ArnD that could prevent it from functioning, thereby unmasking the bacteria and leaving them susceptible to antibiotics.