How S. aureus spreads resistance to antibiotics

Infection by S. aureus is a serious threat in hospitals worldwide. Now, scientists have identified a key component of the machinery that allows Staphylococcus aureus to transfer genes that confer antibiotic resistance. Halting the spread of resistant bacterial strains is one of the strategies available to tackle hospital infections.

Antibiotic resistance of the bacterium Staphylococcus aureus is responsible for 11,300 deaths a year in the United States alone -- a figure that corresponds to half of all deaths caused by gram-positive resistant bacteria in that country. Such high mortality is related to the speed at which the bacterium acquires resistance to antibiotics. A study performed at the Institute for Research in Biomedicine (IRB Barcelona) and involving the collaboration of the Centro de Investigaciones Biológicas (CIB-CSIC) in Madrid has identified the key component of the machinery that S. aureus uses to acquire and transfer genes that confer resistance to antibiotics.

Horizontal gene transfer involves machinery in which the relaxase, an enzymatic protein, is a key component. Thanks to the 3D resolution of the structure of the complex formed by the relaxase with a fragment of the plasmid DNA, the researchers have identified that an amino acid histidine is a pivotal element in the DNA processing and thus in the transfer and the spread of resistance.

"What we have discovered is that the relaxase of diverse strains of S. aureus differs because it uses an amino acid that is not used by any other relaxase that we know of," explains the first author of the study, Radoslaw Pluta, former "la Caixa" PhD student at IRB Barcelona, and currently a postdoctoral researcher at the International Institute of Molecular and Cell Biology in Warsaw, Poland.

Histidine is the catalytic residue that allows the relaxase to cut DNA, bind to it, and stretch one of the two strands and take it into the receptor bacterium, where the strand replicates to form a double strand of the plasmid again. This new plasmid now holds the resistance genes and the machinery to transfer them to another bacterium. The scientists indicate that this catalytic histidine is present in the relaxases of 85% of the strains of Staphylococcus aureus.

To test whether histidine is decisive in horizontal gene transfer,, researchers in Manuel Espinosa's group at the CIB-CSIC, who participated in the study, replaced it by a different amino acid and confirmed that it prevents transfer in culture dishes.

The mutation of histidine does not kill that bacterium but rather prevents gene transfer. How could this mechanism be exploited to fight infections? This requires further study.

See:

Radoslaw Pluta, D. Roeland Boer, Fabián Lorenzo-Díaz, Silvia Russi, Hansel Gómez, Cris Fernández-López, Rosa Pérez-Luque, Modesto Orozco, Manuel Espinosa and Miquel Coll. Structural basis of a novel histidine-DNA nicking/joining mechanism for gene transfer and promiscuous spread of antibiotic resistance. Proceedings of the National Academic of Sciences, July 2017 DOI: 10.1073/pnas.1702971114

Posted by Dr. Tim Sandle