Innate mechanism protects bacteria from last-resort antibiotic

Last-resort antibiotics such as polymyxin are used for bacterial infections when conventional antibiotics fail. However, new research findings show that bacteria have an innate mechanism that protects them from polymyxin. This becomes clear in a recent study by Dr Anna Lena Jung from the German Centre for Lung Research (DZL) at the Philipps University of Marburg.

The researchers analysed the behaviour of the last-resort antibiotic polymyxin against the bacterium Klebsiella pneumoniae, a pathogen that can cause severe pneumonia. Klebsiella pneumoniae is particularly dangerous for patients with a weakened immune system. The bacterium is also showing increasing resistance to many conventional antibiotics, which is why the WHO has categorised it as a particular threat.

The study by PhD student Marie Burt and colleagues revealed that when Klebsiella pneumoniae is given polymyxin, it releases more vesicles that intercept the antibiotic and prevent it from attacking the bacterial cell membrane and drilling harmful holes in the bacteria's membrane. Remarkably, these vesicles protect the producing bacteria and neighbouring sensitive microbes that have not activated this protective mechanism. These can also be bacteria from another family, for example, Pseudomonas aeruginosa.

Insufficient dosing options

The polymyxin doses used by the researchers for their investigations correspond to the concentrations reached locally in the lungs when patients are treated with the antibiotic. At this dosage, the concentration can be so low that the bacteria can activate their protective mechanism and safeguard themselves through increased vesicle release. A higher dosage of the last-resort antibiotic is impossible, as it damages the kidneys.

"Our results show that it can be problematic to resort to polymyxin in an emergency," warns Dr Anna Lena Jung. "The bacteria can use this mechanism to render the antibiotic ineffective, even for sensitive pathogens. This complicates the treatment options considerably."

The work was carried out as part of the LOEWE priority "Diffusible Signals" funded by the state of Hesse at the Institute of Lung Research in collaboration with three DZL researchers, Prof Mareike Lehmann, Prof Danny Jonigk and Prof Bernd Schmeck. In addition, there was cooperation with researchers from SYNMIKRO and the Max Planck Institute for Terrestrial Microbiology in Marburg.

Active interception mechanism

Mass spectrometric analyses showed that the bacteria actively change the composition of the vesicle envelope under antibiotic stress so that less lipid A is present. This seems paradoxical, as lipid A is the most important target for polymyxin on the bacterial surface. At the same time, however, the bacteria release so many more vesicles that there is a lot of lipid A and, therefore, many binding sites for the polymyxin in the environment. The antibiotic is intercepted, and the dose of free active ingredient is reduced so that the bacteria can survive and continue to multiply.

Alternative to genetic resistance

This interception mechanism only occurs in Klebsiellae, which have been tested as polymyxin-sensitive before therapy. There are also bacteria that are already resistant to this antibiotic due to a genetic modification. In these bacteria, the gene for lipid A is altered so that polymyxin can no longer bind to it and, therefore, cannot drill holes in the bacterial surface. Therefore, they do not perceive any stress during treatment with polymyxin and do not increase the amount of vesicles released.

"For future treatment options, we want to understand even better what bacteria register as stress to develop antimicrobial peptides that do not trigger stress-induced protective mechanisms," says Jung. Research is urgently needed, given the increasing antibiotic resistance.

Original publication: Burt M, Angelidou G, Mais CN, et al. Lipid A in outer membrane vesicles shields bacteria from polymyxins. J Extracell Vesicles. 2024;13(5):e12447. doi: 10.1002/jev2.12447