Some commonly used antibiotics accelerate resistance

Antibiotics that impede DNA replication are commonly used, but appear to accelerate the development of resistance. This was recently discovered by the research team headed by molecular geneticist Jan-Willem Veening from the University of Groningen. ‘Doctors must be aware of this, particularly when treating patients with a history of antibiotic resistance,’ he warns. Veening’s findings are to be published in the leading journal Cell on 10 April 2014.

Veening and his team conducted research into Streptococcus pneumoniae (pneumococcus). These bacteria colonize the nasopharynx of many people without causing any real harm. However, the bacteria can also cause serious infections, such as pneumonia, meningitis, ear infections and sepsis. Nearly a million children throughout the world die from pneumococcal infections every year. Increasingly more strains are becoming resistant to antibiotics, causing a major problem for effective treatment.

Important knowledge

Although bacteria are known to acquire resistance to some types of antibiotics more easily than to others, the exact mechanism behind this has always been a mystery. Jan-Willem Veening: ‘In this research, we show at the molecular level how and why certain antibiotics (those that impede DNA replication) induce what is known as the competence process. This knowledge is important when developing new antibiotics, but also for doctors treating patients with a history of antibiotic resistance. They should seriously consider whether or not to choose this type of antibiotic.’

Competence

‘Antibiotic resistance can spread like wildfire,’ explains Veening. ‘This is largely because of a mechanism known as competence, which enables bacteria to take up DNA from their surroundings. This can be highly beneficial to bacteria: in difficult conditions, DNA from the surroundings sometimes has the exact characteristics that the bacteria need to survive. This helps them to acquire resistance to all kinds of antibiotics.’

Replication process stops

The antibiotics that impede the replication process of the bacterial DNA appear to be the very ones that activate this competence mechanism. Veening: ‘The DNA of a bacterium is like a circle. DNA replication starts at one particular point within the circle. The antibiotics we tested, such as trimethoprim, mitomycin C and fluoroquinolones like ciprofloxacin, block this replication process. But they do not do this radically; the replication process takes a while to stop. The genes near to the origin of replication will have already been replicated by then, so a higher proportion of these genes will be present in the cell.

After analysing these genes, we discovered that they are precisely the genes that activate the competence mechanism, meaning that antibiotics of this type increase the uptake of foreign DNA, including possible resistance genes. Antibiotics that impede bacterial growth in other ways, by blocking the growth of the cell wall for example, do not activate the competence mechanism.’

Universal mechanism

The mechanism whereby the antibiotics that impede DNA synthesis also activate the competence process appears to be universal in bacteria. Veening: ‘In addition to S. pneumoniae, we also studied gene expression in other bacteria, including Staphylococcus aureus (which causes skin infections), the gut bacteria Escherichia coli and Bacillus cereus (which causes food-borne illnesses). In every case, genes near to the origin of replication became extra active under the influence of these types of antibiotic.’

Watch the video on Veening's research

Curriculum Vitae

Jan-Willem Veening (Vries, 1978) studied molecular biology at the University of Groningen. After obtaining a PhD from this university, he worked as a postdoctoral research fellow at the Centre for Bacterial Cell Biology of Newcastle University (UK). Veening has headed his own research group in Groningen since 2009, specializing in research into Streptococcus pneumoniae. The group operates as part of the Groningen Biomolecular Sciences and Biotechnology Institute (GBB) of the University of Groningen.

Note for the press

-             The article will be published on 10 April 2014 in the leading journal Cell, under the title: Antibiotic-Induced Replication Stress Triggers Bacterial Competence by Increasing Gene Dosage near the Origin .

-             More information: Jan-Willem Veening