Human histones show promise in fighting bacterial infections

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Antibiotics have saved millions of lives from infectious diseases and are considered one of the most important discoveries of the 20th century. However, as the use (and abuse) of antibiotics has increased over the years, many bacteria have developed resistance to these drugs.

Bacterial resistance to antibiotics is a global crisis that hampers the treatment of common infections and is estimated to be responsible for at least 1.27 million deaths worldwide.

Pathogens such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa have developed resistance to multiple antibiotics, increasing mortality rates, lengthening hospital stays, and driving up health care costs. Without new antimicrobial strategies, it is estimated that resistant infections could cause 10 million deaths per year worldwide by 2050.

In a recent study, scientists led by Eduard Torrents, principal investigator of the "Bacterial infections: antimicrobial therapies" group at the Institute for Bioengineering of Catalonia (IBEC) and associate professor at the University of Barcelona (UB), provide results that could help develop more effective treatments to combat bacterial resistance.

In the study, published in the journal mSystems, they have described that human histones have antimicrobial activity against different bacteria, including biofilms of Pseudomonas aeruginosa, one of the six most resistant bacteria in the world. This work was developed in collaboration with Dr. Albert Jordan of the CSIC and Dr. Alicia Roque and Dr. Inmaculada Ponte of the Autonomous University of Barcelona (UAB).

Histones are key proteins in the organization and regulation of DNA in all eukaryotic cells, i.e. cells in which DNA is contained in a nucleus. This includes fungi, plants and animals. However, in addition to this function, it has been shown that in certain situations histones of subtype H1 can be released outside the cell and exert antimicrobial activity against bacteria, fungi, parasites and viruses.

This activity is mainly attributed to the binding of histones to the membranes surrounding the microorganisms, causing damage that ultimately leads to their death.

The researchers analyzed the antimicrobial activity of three subtypes of human histone H1 against different bacteria, and specifically observed a reduction of up to 70% in the number of bacteria after treatment in P. aeruginosa. Furthermore, the combination of histones with the antibiotic ciprofloxacin had a greater effect than when each was administered separately, opening the door to the development of more effective treatment cocktails.

The research team also studied histone activity against P. aeruginosa biofilms and found a 30% reduction in bacterial mass. Biofilms are communities of microorganisms, including bacteria, fungi and viruses, that adhere to living or inert surfaces, such as tissues, organs or medical devices.

Their peculiarity lies in the secretion of an extracellular matrix that encapsulates and protects the microorganisms, hindering the action of the immune system and antibiotics, making them particularly difficult to treat.

"These findings suggest that the use of histones or parts of these proteins, either alone or in combination with antibiotics or other molecules with antimicrobial activity, is a promising alternative to combat acute and chronic infections caused by pathogens such as P. aeruginosa and other multidrug-resistant bacteria," said Eduard Torrents.

The results were confirmed in in vivo tests on wax worms (Galleria mellonella) infected with P. aeruginosa. Infected larvae treated with the histones showed an increase in survival time compared to untreated larvae. Furthermore, the treatment did not cause any toxic or adverse effects.

The results obtained are particularly relevant because biofilms are highly resistant to antibiotics and cause severe infections. It is crucial to identify new molecules with antimicrobial activity as well as new mechanisms of action against biofilms in order to develop more effective therapeutic strategies.

The next steps include determining the molecular part of the histone with the most antimicrobial capacity and validating the use of histones in the clinic.

More information: Betsy Verónica Arévalo-Jaimes et al, Antimicrobial and antibiofilm activity of human recombinant H1 histones against bacterial infections, mSystems (2024). DOI: 10.1128/msystems.00704-24

Journal information: mSystems

Provided by Institute for Bioengineering of Catalonia (IBEC)