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Disease and treatment

Sneaking antibiotics into multidrug-resistant bacteria

The increasing resistance of bacteria to multiple antibiotics has triggered a new phase in humanity’s never-ending battle against bacterial infections. The excessive use of otherwise effective antibiotics has required developing new weapons. Peptide nucleic acids that are DNA mimics can inhibit specific protein synthesis of bacteria. The challenge is to sneak these molecules into the bacteria to inhibit their growth without also destroying our own cells.

In 2013, antibiotic-resistant bacteria caused 700,000 people to die worldwide, and the number of multidrug-resistant bacteria strains is increasing rapidly. With the first reports of resistance to the last antibiotic resort of hospitals, such as carbapenems, the threat of worldwide multidrug resistance is enormous. A Danish research group is now actively focusing on developing a new alternative weapon against bacteria.

According to Peter Eigil Nielsen, Professor, Department of Cellular and Molecular Medicine, University of Copenhagen, “Unlike standard antibiotics that utilize general differences between bacteria and their host, the new antibiotics very specifically target certain types of bacteria. Using molecules that are a chemical hybrid between DNA and a peptide, we can specifically inhibit bacteria from producing certain essential proteins, thereby enabling us to kill the bacteria effectively.”

Peptide nucleic acids (PNA) appear to be useful in combating pathogenic bacteria. PNA molecules resemble DNA molecules in structure but have a protein-like backbone. This means that PNAs bind more strongly to DNA and RNA molecules and have exquisite biological stability.

“PNA can bind very specifically and strongly to a corresponding RNA molecule, and we can utilize this property in combating bacteria. Cells transcribe DNA to RNA, which acts as the instruction code for protein synthesis. Short PNA molecules targeting selected RNA molecules can inhibit synthesis of the protein for which this RNA codes in the bacteria,” says Peter Eigil Nielsen.

Guided access

The initial task involves identifying suitable essential bacterial proteins so that the bacteria will not be able to survive the inhibition of their synthesis. In the current studies, the researchers successfully targeted fatty acid biosynthesis in Gram-negative bacteria such as Escerichia coli and Pseudomonas aeruginosa.

“Since bacteria are genetically very different from humans, PNA molecules can be designed to specifically target bacterial and not human genes, and thus there is very little risk that PNA molecules will also affect the genes in our own cells,” says Peter Eigil Nielsen.

The greatest challenge of this new technology is actually completely different.

According to Peter Eigil Nielsen, “PNA molecules are too big and have properties that prevent them from penetrating the cell membranes of bacteria. We are therefore working intensely on finding transport molecules that can effectively help to transport PNA into bacteria without toxicity to people, and to understand how this transport takes place.”

Understanding is not enough

The first-generation PNA antibiotics that can specifically kill multidrug-resistant bacteria have been developed but they are neither effective nor safe enough as drugs. Nevertheless, the new PNA weapon has one enormous advantage.

“Current antibiotics exploit only a few molecular mechanisms in bacteria, and as soon as some bacteria develop resistance and this spreads, all antibiotics that depend on this mechanism are no longer effective. With PNA antibiotics, we can not only select numerous new biological mechanisms against which no resistance has been discovered, but we can also in several cases target them against the mechanisms that are responsible for the existing resistance and thereby eliminate it,” adds Peter Eigil Nielsen.

Finally, antisense technology is a generic platform. This means that second-generation antibiotics, whose general pharmaceutical properties are similar to first-generation antibiotics, can be developed very easily based on the same principles and be used against new bacterial mechanisms in the never-ending battle against new types of multidrug resistance.

“In the next 3–6 years, the development of these new PNA-based antibiotics is planned to evolve such that a pharmaceutical company can take over and carry out preclinical and subsequently clinical trials that hopefully will result in a new generation of antibiotics that can effectively combat infections with multidrug-resistant bacteria,” concludes Peter Eigil Nielsen.

Antibacterial peptide nucleic acid−antimicrobial peptide (PNA−AMP) conjugates: antisense targeting of fatty acid biosynthesis” has been published in Bioconjugate Chemistry. In 2017, the Novo Nordisk Foundation awarded a Challenge Programme grant to Peter Eigil Nielsen for the project Antibiotic Resistance and Alternative Antibiotics.

Peter E. Nielsen
Professor, dr. scient.
The research interests are centered around the DNA mimic PNA (peptide nucleic acid), and the chemical biology and medicinal chemistry properties and applications of derivatives of this molecule. This includes drug discovery (antisense antibiotics, muscular dystrophy, cystic fibrosis), gene targeting and antisense principles in general and cellular and in vivo delivery and administration of biopharmaceuticals. Additional interests cover origin of life prebiotic systems and the effects of oxidative stress on cellular RNA.