Modification of vancomycin to overcome bacterial resistance

• Applicants: Professor Dr. Walter Mier; Privatdozent Dr. Knut Ohlsen
• Subject Area: Pharmacy
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 436573923

While there are numerous drugs available for the therapy of bacterial infections, there is only a few of compounds capable to serve as last resort for severe infections. Moreover, as the number of cellular targets vulnerable by drugs is limited, the endless chase: loss of drugs caused by resistance and the development of novel compounds results in the exhaustion of the pool of essential compounds. Most of the drugs that have been perfected to a target originate from eternal natural evolution. The continuous depletion of this pool is the main reason why efficacious antibiotics fail upon occurrence of multiresistant microbial strains. Consequently, the key principle of antibiotics development should be the optimization of the seasoned compounds to break development of resistance either by attacking bacteria using multiple mechanisms and/or reinforcement of the mode of action.Vancomycin is the pivotal antibiotic for the treatment of multi-drug resistant infections caused by Gram-positive bacteria. Unfortunately, vancomycin-resistant bacteria have become an increasingly difficult-to-treat cause of nosocomial infections. In order to obtain vancomycin derivatives that are able to overcome vancomycin resistance, a variety of derivatives have already been synthesized by the conjugation of specific polycationic peptides at four different sites of vancomycin and studied with respect to their in vitro antimicrobial activity, demonstrating the potential by breaking the main types of vancomycin resistance (vanA, vanB, vanC) on different vancomycin-resistant enterococci. On an E. faecium ATCC51559, the current lead compound (FU002) showed a 1926-fold reduced molar MIC. This high in vitro efficiency could already be confirmed in vivo: FU002 showed significant reduction of the CFU in a therapeutic sepsis-mouse-model.Furthermore, the novel conjugates may offer high benefit due to their low in vitro cytotoxicity as proven by cytotoxicity assays in several cell lines (kidney, liver, blood). The therapeutic potential of vancomycin is limited by its nephrotoxicity. In contrast, the novel compounds do not show accumulation in the kidneys and might be designed to allow higher target to non-target ratios.Based on these promising first results, in this project a library of vancomycin-modified compounds shall be synthesized and characterized by a variety of in vitro and in vivo tests (e.g. MIC, cytotoxicity, pharmacokinetics, biodistribution studies). For this purpose an enterococci- mouse model shall be established by the Ohlsen lab in order to demonstrate the efficiency of treatment of vancomycin resistant bacteria. Additionally, possible resistance mechanisms (development and induction) shall be investigated accompanied by the evaluation of the mode of action of the novel vancomycin-modified derivatives. Due to their lab equipment and the unique synergistic expertise of the Mier and Ohlsen lab, both working groups represent ideal partners for this project.

• DFG Programme: Research Grants