What are antibiotics?
Antibiotics are used to cure bacterial infections in animals and people. Antibiotics are agents that kill germs without harming animals or people. Antibiotics have no effect on viruses. Bacteria have various ways to develop resistance to antibiotics.
Antibiotic resistance is not a new discovery
Alexander Fleming discovered the technology for making penicillin, the world’s first safe antibiotic, in 1928. Already in 1945, three years after it came on the market, he stated that the world would see development of resistance.
Article series
The University of Oslo is undertaking a number of projects in the field of life sciences aiming to address the increasing problem of antibiotic resistance.
This is the second in a series of three articles from UiO:Life Science on this topic.
Read the first article: Better digital management is needed to control the use of antibiotics.
Part of an interdisciplinary community at UiO
Pål Rongved’s research group is part of an interdisciplinary strategic research initiative, the Centre for Integrative Microbial Evolution (CIME) at the Faculty of Mathematics and Natural Sciences. The objective of strategic research initiatives is to encourage collaboration across academic disciplines to drive research forward. In CIME, Rongved exchanges knowledge and competence with others who are working with basic research on bacteria.
‘CIME is important because it permits us to work alongside others who from various perspectives seek to understand how bacteria work. For example, we have some who study the evolution of bacteria and how they develop genetically. One of the advantages bacteria enjoy when it comes to antibiotic resistance is their ability to change their genes and adapt. They can change their genetic material in cycles of only a few years. For humans, this requires several thousand years.’
Ever since the 1940s when the antibiotic penicillin was introduced, we have been able to use antibiotics to cure bacterial infections. Now, a growing number of bacteria are becoming resistant to antibiotics, rendering these drugs ineffective for treatment.
‘Penicillin is one of the greatest revolutions in medical history, but all antibiotics sooner or later cause development of resistance. For this reason, the pharmaceutical industry has been reluctant to put any effort into new products, and no genuinely new antibiotics have been launched for the last twenty years. We are therefore entering a post-antibiotic era, where we are back to the time before there were any antibiotics that could cure bacterial infections,’ Pål Rongved explains.
He is professor at the School of Pharmacy, Faculty of Mathematics and Natural Sciences at the University of Oslo (UiO), and is one of UiO’s researchers in life sciences who are working with issues of antibiotic resistance.
Could a molecule that upsets the zinc balance in the bacteria be a solution?
Rongved and his research group are seeking to identify new agents that can be used in the struggle against antibiotic-resistant bacteria. Their approach is to use a molecule, a so-called zinc chelator, that can selectively bind the metal zinc and upset the zinc balance in the bacteria.
Beta-lactam-type antibiotics such as penicillin have increasingly become ineffective because an enzyme in the bacteria – beta-lactamase – destroys the antimicrobial activity of the antibiotic.
Rongved explains that their zinc chelators upset a sub-group of lactamases – metallo-beta-lactamases – that depend on zinc, thus rendering the enzymes unable to harm the effect of the antibiotic.
‘Our zinc chelator is what we refer to as an adjuvant. This means that it needs to be ingested along with another molecule, in this case a beta-lactam antibiotic. Our chelator has a large reinforcement effect on commercial antibiotics when tested on various bacteria – including those that in principle are resistant to the antibiotic.’
Long experience with metal compounds
But given that nobody else has succeeded in creating new antibiotics in two decades, how can it be that Rongved puts such faith in their approach, and from where did he have the idea to use his zinc chelator against bacteria?
‘I have undertaken research on metal compounds for 25 years, including many years in the pharmaceutical industry. In 2009, we tried to determine whether we could inhibit cancer cells by using zinc chelators to upset their zinc balance,’ he says.
He goes on to say that their entry into the field of antibiotic resistance and the use of zinc chelators on bacteria came about when they became aware of the researcher Ørjan Samuelsen and his colleagues at the Competence Centre for detection of antibiotic resistance (K-res) at the University Hospital of North Norway (UNN), who studied the metallo-beta-lactamases that bacteria use to destroy antibiotics – and that these contained two zinc atoms.
‘When we tested our zinc chelator on the bacteria, we were surprised to find that it had antimicrobial properties. The chelator upset the zinc balance in the bacteria, thus inhibiting the metallo-beta- lactamase.
Further tests are needed
Bacteria and our cells share the need for an optimal zinc balance in order to function normally. Humans have approximately 6000 enzymes that depend on zinc. It is therefore also extremely important to make sure that the zinc chelator will not harm our own cells.
The researchers have equipped the zinc chelator with a target-seeking component causing it to concentrate mainly on bacteria and less on human cells. They have now started to test the zinc chelator on human cells in the laboratory, and things are looking good so far. Soon they will start tests on a larger scale.
Many have faith in the project
Rongved has been granted financial support from several quarters. The Research Council of Norway has granted NOK 7.3 million in support to the ZinChel project through its BIOTEK 2021 programme, Norway’s large biotechnology programme. In addition, the Novo pre-seed fund in Denmark has granted DKK 2.5 million to the project. Rongved has also been invited to participate in a large European project being led by Uppsala. In this context he has started talks with the pharmaceutical company GlaxoSmithKline.
Rongved has applied for a patent on the technology through UiO’s commercialization company Inven2. Now he is among those who will participate in Inven2’s business programme.
