Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
| Autor: | Katheryn Lh Hagart, Michele Becce, Akshay Sabnis, Despoina A. I. Mavridou, R. Christopher D. Furniss, R.A. Murphy, Jane C. Davies, Thomas B. Clarke, Andrew M. Edwards, Gerald Larrouy-Maumus, Lindsay E. Evans, Molly M. Stevens, Anna Klöckner |
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| Přispěvatelé: | Medical Research Council (MRC), Wellcome Trust, Commission of the European Communities, Cystic Fibrosis Trust |
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Life Sciences & Biomedicine - Other Topics 0301 basic medicine Lipopolysaccharide Polymyxin ANTIBACTERIAL ACTIVITY Antibiotics SUSCEPTIBILITY PULMONARY 0601 Biochemistry and Cell Biology medicine.disease_cause chemistry.chemical_compound INFECTION polycyclic compounds Biology (General) Respiratory Tract Infections Microbiology and Infectious Disease 0303 health sciences biology Chemistry Escherichia coli Proteins General Neuroscience lipopolysaccharide General Medicine MICROBIOTA Anti-Bacterial Agents 3. Good health Pseudomonas aeruginosa Medicine Drug Therapy Combination Female lipids (amino acids peptides and proteins) Bacterial outer membrane Life Sciences & Biomedicine Research Article medicine.drug Gram-negative bacteria Membrane Fluidity QH301-705.5 medicine.drug_class Science infectious disease 030106 microbiology Peptides Cyclic General Biochemistry Genetics and Molecular Biology Microbiology 03 medical and health sciences Pseudomonas Drug Resistance Bacterial Escherichia coli medicine Animals Humans Pseudomonas Infections POLYMYXIN-B GRAM-NEGATIVE BACTERIA Mode of action Biology phospholipids 030304 developmental biology Microbial Viability Science & Technology CYSTIC-FIBROSIS General Immunology and Microbiology Colistin 030306 microbiology business.industry Cell Membrane microbiology E. coli biochemical phenomena metabolism and nutrition biology.organism_classification Mice Inbred C57BL Disease Models Animal 030104 developmental biology bacteria OUTER-MEMBRANE business RESISTANCE Bacteria Polymyxin B |
| Zdroj: | eLife eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| Popis: | Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes. eLife digest Antibiotics are life-saving medicines, but many bacteria now have the ability to resist their effects. For some infections, all frontline antibiotics are now ineffective. To treat infections caused by these highly resistant bacteria, clinicians must use so-called ‘antibiotics of last resort’. These antibiotics include a drug called colistin, which is moderately effective, but often fails to eradicate the infection. One of the challenges to making colistin more effective is that its mechanism is poorly understood. Bacteria have two layers of protection against the outside world: an outer cell membrane and an inner cell membrane. To kill them, colistin must punch holes in both. First, it disrupts the outer membrane by interacting with molecules called lipopolysaccharides. But how it disrupts the inner membrane was unclear. Bacteria have evolved several different mechanisms that make them resistant to the effects of colistin. Sabnis et al. reasoned that understanding how these mechanisms protected bacteria could reveal how the antibiotic works to damage the inner cell membrane. Sabnis et al. examined the effects of colistin on Escherichia coli bacteria with and without resistance to the antibiotic. Exposing these bacteria to colistin revealed that the antibiotic damages both layers of the cell surface in the same way, targeting lipopolysaccharide in the inner membrane as well as the outer membrane. Next, Sabnis et al. used this new information to make colistin work better. They found that the effects of colistin were magnified when it was combined with the experimental antibiotic murepavadin, which caused lipopolysaccharide to build up at the inner membrane. This allowed colistin to punch more holes through the inner membrane, making colistin more effective at killing bacteria. To find out whether this combination of colistin and murepavadin could work as a clinical treatment, Sabnis et al. tested it on mice with Pseudomonas aeruginosa infections in their lungs. Colistin was much better at killing Pseudomonas aeruginosa and treating infections when combined with murepavadin than it was on its own. Pseudomonas aeruginosa bacteria can cause infections in the lungs of people with cystic fibrosis. At the moment, patients receive colistin in an inhaled form to treat these infections, but it is not always successful. The second drug used in this study, murepavadin, is about to enter clinical trials as an inhaled treatment for lung infections too. If the trial is successful, it may be possible to use both drugs in combination to treat lung infections in people with cystic fibrosis. |
| Databáze: | OpenAIRE |
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