Staphylococci cause a wide range of diseases in human and animals such as skin infections, pneumonia, food poisoning and blood poisoning. They are notorious for their ability to develop resistance to antibiotics almost as soon as they are approved for clinical use and are the scourge of hospitals where they can cause death in patients admitted for other diseases. The multiple antibiotic resistance repressor (MarR) family proteins in Staphylococci function as regulators of protein expression and confer resistance to multiple antibiotics. Diverse mechanisms such as biofilm formation, drug transportation, drug modification etc. are associated with the resistance.
In this study, former vice President Andrew H.-J. Wang and his team revealed the crystal structures of the S. aureus MarR homolog SAR2349 and its complex with antibiotic and salicylate. The structure of SAR2349 shows, for the first time, that a MarR protein can interact directly with different classes of ligands simultaneously and highlights the importance and versatility of regulatory systems in bacterial antibiotic resistance. The 3D structures of TcaR from S. epidermidis in complex with antibiotics are also investigated. The crystal structures of TcaR and SAR2349 complexes illustrate a general antibiotic regulated resistance mechanism that may extend to other MarR proteins. This finding provides further understanding of antimicrobial resistance mechanism in pathogens and for the strategies to develop new therapy in pathogens.
The slide show below shows that MarR proteins such as TcaR bind to DNA to prevent the expression of biofilm in Staphylococci under normal conditions. When antibiotics enter, significant conformational changes of TcaR on the DNA binding domains will be exerted to induce the inactivation and the departure of TcaR from DNA. This results in increased expression of biofilm which defenses antibiotic treatment.
This research was conducted and financed by Academia Sinica and the grants from the National Research Program for Biopharmaceuticals, a project funded by the National Science Council of Taiwan. The authors of the research article are Yu-Ming Chang (first author), Cammy K.-M. Chen, Tzu-Ping Ko, Masatoshi Weiting Chang-Chien and Andrew H.-J. Wang. Their research was published on June 2013 in Acta Cryst. D, one of the top journals in crystallography.
Link to online abstract : http://www.ncbi.nlm.nih.gov/pubmed/23695258
Authors : Chang YM, Chen CK, Ko TP, Chang-Chien MW, Wang AH
Updated : 2013.06.27