Understanding antibiotic entry into bacteria

点击翻译按钮获取中文摘要

Antibiotics have made possible the treatment and cure of life-threatening bacterial infections. Unfortunately, the rise of antibiotic-resistant "superbugs" is dramatically undermining the effectiveness of these important drugs, a problem that represents one of the current greatest threats to global public health. A crucial aspect of addressing the problem will involve the discovery and development of novel antibiotics active against bacteria that have become resistant to our existing antibiotics. However, a major scientific challenge stands in the way of achieving this aim. Although it is now feasible to identify or make new chemical compounds that interfere with the correct functioning of the biological machinery of bacteria (a requisite property of any potential antibiotic), these compounds are in the main unable to cross the membrane(s) that surround bacteria to reach that machinery. If we knew how to modify these compounds to effectively deliver them into bacteria, they would have potential as new antibiotics. This proposal seeks to provide the fundamental scientific knowledge to make such an approach possible. By understanding how small molecules like antibiotics enter bacteria - a phenomenon about which we know very little at present - we will gain the necessary strategic intelligence to allow us to rationally generate new antibiotics. The project will take two complementary approaches to achieve this. The first of these will employ a technique known as liquid chromatography-mass spectrometry (LC-MS) to directly measure the ability of a large and diverse collection of small molecules to penetrate into bacteria. From the results of this study, we will be able to determine what physical and chemical properties a small molecule must have to allow it to enter bacteria, allowing us to formulate a set of rules that can be applied to guide the generation of new antibiotics. The second approach will investigate the mechanism or process by which established antibiotics actually cross the membrane(s) of bacteria. The current view is that, since membranes are fluid in nature, most such compounds simply drift or diffuse across. However, we have evidence to suggest that in fact most (perhaps all) antibiotics take advantage of protein 'pumps' in the membrane(s) that bacteria ordinarily use to import things such as nutrients from the environment. By examining what impact artificially altering the number or levels of these pumps in bacteria has on the ability of antibiotics to enter, we aim to more clearly demonstrate the role of these pumps in antibiotic entry. The implications of the idea that antibiotics enter bacteria via such pumps are considerable. For example, it would mean that for antibiotics to get into bacteria they need to have similar physical or chemical features to 'desirable' compounds that bacteria import from the environment; features that allow them to 'hijack' the corresponding pumps. Furthermore, it would offer a strategy to make new antibiotics by designing compounds that have regions of similarity to natural compounds that bacteria import.