Resistance toward CHX and cross-resistances toward antibiotics in oral bacteria

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Antibiotic resistance has attracted strong medial interest during the last two decades, thus stimulating research in this area. Conversely, much less attention has been given to the problem of resistance toward antiseptics and biocides. In the field of dentistry, chlorhexidine (CHX) is considered as gold-standard antiseptic, thus being commonly used in clinics and also included in a wide range of oral care consumer products. As CHX is also commonly used in other medical fields (e.g. for decolonization of MRSA), resistance towards this antiseptic would have tremendous consequences for the whole medical sector.Although there have been reports on the risk of cross-resistances between CHX and medically relevant antibiotics, this issue has not been investigated systematically so far. With regard to resistance towards CHX, one has to clearly distinguish between phenotypic adaptation and acquired resistance, which is genetically defined and therefore stable. In oral biofilms areas with sub-inhibitory concentrations of CHX that potentially lead to development of resistances in bacteria can easily arise upon application of CHX-containing products. As potential resistance mechanisms are similar to those for antibiotics (e.g. efflux pumps), further development of cross-resistances is possible.Therefore, the aim of this joint proposal of the Departments of Conservative Dentistry and Periodontology at the University Medical Centers of Regensburg and Freiburg is to investigate the development of resistance in oral bacteria upon repeated exposure to CHX phenotypically and genetically. For this purpose, oral isolates shall be repeatedly exposed to CHX in vitro and investigated for a consequent phenotypic adaptation. These isolates shall be assessed for development of cross-resistances phenotypically as well as molecular-genetically and changes in their biofilm-forming capacities shall be evaluated. Selected isolates with clear phenotypic resistance towards CHX shall further be characterized by whole genome sequencing and mRNA sequencing as compared to their respective wildtype strains.Furthermore, development of resistance towards CHX shall also be investigated in vivo in oral biofilms of patients that need to use CHX multiple times per day for at least 4 weeks upon periodontal surgery. Shotgun-metagenome analyses shall be employed to assess potential microbiome shifts as well as the equipment with resistance genes.The findings from this project shall allow for assessing the risk of a spread of resistance towards CHX and concomitant cross-resistances towards antibiotics, thus potentially being relevant for the all fields within the sectors of dentistry and medicine.