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Multi resistant bacteria & phospholipids

Research Article

The development of new antibiotics alone is not believed to stop multi resistant bacteria. A new strategy is emerging.

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Henri M Deda
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Henri Deda holds a degree in Molecular Bioengineering and Business Administration. He is motivated to provide inclusive, scientific answers.


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Pseudomonas aeruginosa is a multi resistant bacterium
• Lipidomics proved the role of lipid metabolism in the bacterium’s antibiotics resistance
• Disturbing lipid metabolism increased impact of antibiotics

AFTER the development of vaccines, the discovery and description of the first antibiotic compound in 1928 was the next milestone in pharma research, and the development of further antibiotics helped modern medicine thrive and flourish. Antibiotics prevent infections from spreading and help the immune system fight off invading pathogens like bacteria. Their wide-spread use comes with a downside: many bacteria evolved strategies to resist antibiotics thus rendering them ineffective.

A graphic representation of the main cellular mechanisms of antibiotics resistance in bacteria.

While there are alternative and safe antibiotics for most of these resistant pathogens, over time, some bacteria developed resistances to multiple antibiotics or are naturally multi resistant. Thus, medical doctors and researchers are worried about the advancing number of cases involving multi resistant bacteria as such infections are difficult or even impossible to treat.

Besides using antibiotics mindfully to slow down the adaption process of bacteria, and developing new antibiotics, scientists are increasingly exploring a third approach: They are looking for ways to make multi resistant bacteria susceptible to already existing antibiotics (again).

A graph showing the projection of deaths from multiple causes including antimicrobial resistance, cancer, diabetes and other diseases. Antimicrobial resistance is believed to become the leading cause of death by 2050.

Projection of deaths from antimicrobial resistance: multi resistant pathogens are believed to become the leading cause of death by 2050.
Review on Antimicrobial Resistance, UK Department of Health (2016), www.amr-review.org

Breaking antimicrobial resistance mechanisms is a task easier said than done. An approach to accomplish that goal might lie in disturbing bacterial lipid metabolism, a target which many existing antibiotics are addressing, too. A team of researchers led by scientists from the Helmholtz Centre for Infection Research applied global lipidomics analysis to investigate the molecular lipid composition of Pseudomonas aeruginosa, a wide-spread bacterium that can cause diseases like pneumonia, septic shock and other hospital-acquired infections.

The multi resistant bacterium P. aeruginosa is equipped with high natural antibiotic resistance and is known to develop further resistances during therapy making it extraordinarily difficult to overcome. P. aeruginosa is a particular threat to immunocompromised patients and individuals with cystic fibrosis are often affected by a persistent infection with the multi resistant bacteria.

The team of molecular biologists and microbiologists compared two strains of P. aeruginosa – a wild type and a mutant lacking the protein PA3911. As the researchers exposed both strains to a series of antibiotics they discovered that said protein PA3911 is important to the bacterium’s naturally high antimicrobial resistance.

A structural analysis of PA3911 revealed that this protein binds specifically to the lipid phosphatidic acid (PA), a central hub for the biosynthesis of the diverse class of phospholipids, in order to channel the lipid into diverse biosynthetic pathways. Following up on these results, the scientist were interested to investigate the differences in composition of PA lipids and PA metabolism associated lipids in P. aeruginosa to reveal the mode of operation of PA3911.

Scientific graphs showing lipidomic changes of selected lipid classes on class and species level dependent on the phospholipid metabolism associated protein PA3911.

PA3911-dependent lipid profile changes of selected lipid classes on species level: Lipidomics was used to determine the absolute amounts of lipid classes and lipid species of the wild type and the PA3911 mutant strain grown under aerobic and anaerobic conditions. Lipid species (or subclasses) are annotated according to the amount of carbon atoms of the respective fatty acid moiety: total number of double bonds (and/or number of cyclopropylation).
Maike K Groenewold et al., Biochemical Journal (2018), doi: 10.1042/BCJ20180257

A global lipidomics analysis of P. aeruginosa revealed significant differences in levels of PA and PA associated lipids between the wildtype and the mutant strain. Specifically, lipid levels but also composition on molecular level of the lipid classes lyso-phosphatidylcholine, phosphatidylcholine and diacylglyerol showed compelling differences – lipid classes which are all linked to phospholipid metabolism through the central hub PA.

These findings demonstrate how the protein PA3911 maintains phospholipid homeostasis. Knocking out the protein unbalances phospholipid homeostasis and greatly increases susceptibility of P. aeruginosa to many antibiotics, an approach which was discovered and figured out through the combination of research results from antibiotics exposure testing to lipidomics analysis.

Modern medicine from surgery to chemotherapy is scrutinized by the lack of reliable antibiotics to fight off antimicrobial resistant pathogens. Making multi resistant bacteria susceptible to already existing antibiotics (again) is an emerging approach which gains traction through new insights on the molecular level.

Collecting and investigating such information like detailed lipid metabolism and lipid composition data through Lipotype Lipidomics technology, helps infectiology and pharma researchers identify microbial weak spots. This will lead to new approaches and treatment options to overcome infections with high-risk or non-existing treatment options.

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Helmholtz Centre for Infection Research

Logo of the Helmholtz Centre for Infection Research with blue background.

The HZI is Germany’s largest academic institution dedicated exclusively to infectiology. The centre develops new strategies for detection, prevention, and treatment of infections.

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