Development of antiinfective drug molecules and point-of-care infection diagnostics
Author: Dr. rer. nat. Hannelore Meyer
Antiinfective drug molecules
Antibiotic resistances are –again- an increasing and long lasting threat to human health, lives and wellbeing. Loss of antibiotic efficacy is expected to massively increase the number of infection related death cases, to jeopardize many therapies in modern medicine (e.g. complicated surgeries, transplantation and chemotherapy and care for premature infants), to lead to massive increase in health care costs and global loss of productivity and is discussed to pose a threat to social security.
β-Lactam antibiotics are widely applicable and particularly well tolerated, which renders them the most frequently used and most important class of antibiotics, as well as the most lifesaving therapies in modern medicine. The alarming dissemination of β-lactamase resistances of the carbapenemase type, is posing an increasing threat to human health and lives, as these enzymes inactivate all types of classical β-Lactam antibiotics. Moreover, as many carbapenem resistant pathogens in addition express resistances against other classes of antibiotics, treatment options are dramatically limited. The urgent need for novel treatment options for Gram-negative carbapenemase resistant pathogens has recently been emphasized in the published WHO priority pathogens list for R&D of new antibiotics, which summarizes many of these pathogens in the Priority 1 group.
We address this massive threat to patient’s health and lives posed by the Priority 1 group pathogens by developing inhibitors for all types of carbapenemases for clinical use in combination with last resort β-lactam antibiotics (carbapenems). For this we collaborate with HMGU and HZI.
Furthermore, we have established and validated a number of screening assays (FRET-, absorbance- and fluorescence-based) for the development of pathoblockers againstHelicobacter pylori,Staphylococcus aureus, andFrancisella tularensisvirulence targets (in collaboration with Ag Gerhard). The rationale of the pathoblocker approach is to inhibit the interaction of the bacterial pathogen with the human cells or immune system and thereby reduce the infectivity, virulence and/or immune evasion mechanism of the bacteria. The advantage of this approach is the reduction of selective pressure posed by these molecules in comparison to classical antibiotics, which will at least delay resistance formation. Due to increased species specificity of the target – and thus the pathoblockers – resistance dissemination to other pathogen species and side effects by interference with the microbiome are expected to be reduced.
One approach to reduce unnecessary antibiotic prescriptions - and thereby resistance induction - is the development of improved infection diagnostics. The ultimate goal for a successful point-of-care infection diagnostics is the identification of the pathogen and its resistances, discrimination of infection vs. colonization, collection of relevant patient data, high fidelity with specificity and sensitivity > 95% and a turn-around time of < 20 min.
Due to their potentially live threatening outcome of Legionellosis, pulmonary infections are -– frequently treated with macrolide and fluoroquinolone antibiotics, even though infections withLegionella pneumophilaonly account for 5% of all bacterial air way infections. In a BMBF funded project, we currently develop a reliable point-of-care test for Legionella infections in collaboration with a SME partner with the goal to prevent unnecessary antibiotic prescription.
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