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
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
DOI: 10.7554/elife.65836
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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