Molecular mechanisms of antimicrobial peptides: phase changes induced in endotoxic bacterial lipopolysaccharide.
Lead Research Organisation:
King's College London
Department Name: Pharmaceutical Sciences
Abstract
Antibiotics have long been used for treating a variety of diseases in humans. They are generally very useful as drugs because they are able to kill off the disease-causing organisms without producing harmful side effects in patients. Over recent years, however, many of these drugs have become less effective, and in some cases are now totally useless. The reason for this is that the disease-causing organisms have developed a resistance to the drugs / which means quite simply that they have found ways to avoid the drugs' toxic effects.This alarming rise in infections due to drug-resistant bacteria - like MRSA - has given rise to growing public concern, and has prompted a call for new antibiotics that can be used to treat patients infected with the drug-resistant organisms. To trust to luck and hope for some chance discovery of a new drug (as with Fleming's discovery of penicillin, for example) is clearly not satisfactory: the problem of resistance is with us in the clinics now, and must be dealt with more speedily.A more sensible way forward is to design new drugs that work in novel ways, and one such class of compounds that might be exploited are the family of anti-bacterial peptides. Such an approach, of course, requires that we fully understand how these anti-bacterial peptides work, and unfortunately this is not the case. It is thought that the peptides might somehow interact with the bacterial outer surface - most likely with the fever-causing molecular building-blocks known as lipopolysaccharides. Precisely how the peptides interact with these lipopolysaccharides, however, is not yet established.In the research to be carried out at King's College London, the aim is to find out how anti-bacterial peptides work, looking in particular at the nature of their interaction with the bacterial lipopolysaccharides. The research will involve using microscopic, bubble-like structures known as liposomes or very thin layers of material which are the thickness of only one or two molecules, prepared using different bacterial lipoploysaccharides, so that they mimic bacterial cells and their surfaces. These bacterial structure mimics will then be studied using a combination of advanced analytical techniques, looking also at how the membrane structures are changed in the presence of the anti-microbial peptides. From the knowledge gained in these investigations, it is hoped to pave the way for others to design new and improved forms of antibiotic for use against antibiotic-resistant bacterial infections.
Organisations
Publications
Hubbard AT
(2017)
Mechanism of Action of a Membrane-Active Quinoline-Based Antimicrobial on Natural and Model Bacterial Membranes.
in Biochemistry
Bello G
(2016)
The influence of rough lipopolysaccharide structure on molecular interactions with mammalian antimicrobial peptides.
in Biochimica et biophysica acta
Rehal R
(2021)
Lipid domain formation and non-lamellar structures associated with varied lysylphosphatidylglycerol analogue content in a model Staphylococcal plasma membrane.
in Biochimica et biophysica acta. Biomembranes
Rehal RP
(2017)
The influence of mild acidity on lysyl-phosphatidylglycerol biosynthesis and lipid membrane physico-chemical properties in methicillin-resistant Staphylococcus aureus.
in Chemistry and physics of lipids
Junkes C
(2011)
Cyclic antimicrobial R-, W-rich peptides: the role of peptide structure and E. coli outer and inner membranes in activity and the mode of action.
in European biophysics journal : EBJ
Rehal R
(2019)
The pH-dependence of lipid-mediated antimicrobial peptide resistance in a model staphylococcal plasma membrane: A two-for-one mechanism of epithelial defence circumvention.
in European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
Bello G
(2015)
Characterization of the aggregates formed by various bacterial lipopolysaccharides in solution and upon interaction with antimicrobial peptides.
in Langmuir : the ACS journal of surfaces and colloids
Sebastiani F
(2012)
Diffraction studies on natural and model lipid bilayers
in The European Physical Journal Special Topics
Hubbard AT
(2017)
Comparing the action of HT61 and chlorhexidine on natural and model Staphylococcus aureus membranes.
in The Journal of antibiotics
Title | Invisible You |
Description | Mellissa Fisher is an artist whose background stems from an interest in the interrelationships between fine art, illustration and science. Her most recent work consists of a deep exploration of the connections between nature and the human body. She is exhibiting Microbial Me, a microbiological portrait, or bacterial sculpture, developed in collaboration with Dr Richard Harvey and Dr Mark Clements. |
Type Of Art | Artistic/Creative Exhibition |
Year Produced | 2015 |
Impact | Increased collaboration with different artists, including joint applications for Art/Science project funding. |
URL | https://www.edenproject.com/visit/whats-here/invisible-you-the-human-microbiome-exhibition |
Description | This research project set out to study the structures fomed by a speicific kind of bacterial toxin called LPS, (which is responsible to causing septic shock in patients in critical care) and how these structures influence LPS toxicity. We were also interested in the effect that small proteins made by the human immune system (defensive peptides) could neutralise these toxins by altering the structures which they made when complexed together. A theory has been developed to explain how LPS structure and toxicity are related, which states that the formation of multi-layered structures upon interaction with defensive peptides would reduce LPS toxicity. Our findings have shown that many more complex structures are formed by LPS when compled with defensive peptides, than simple multi-layers. These comples structurtes (which resemble webs or nets) appear to be just as effective at reducing toxicity, and as such go against the current theory. The fact that the theory was based upon experimental data obtained from samples which were not prepared under conditions which mimic those encountered in nature (i.e., with excess water) and our experiments were carried out under more appropriate biomimetic conditions, adds validity to our findings. |
Exploitation Route | Our findings will be of use to those scientists working in the field of LPS-indiced sepsis, especially those interested in developing a screening method for testing new anti-endotoxic materials. The highly regular and ordered structures we observed upon complexing LPS with defensive peptides could be used as templates for future nanomaterials. |
Sectors | Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |