High-specific targeted Antibody-Drug Conjugates against Carbapenem-Resistant Acinetobacter baumannii delivered by omics analysis and drug design.

• Applicant: Dr. Bipasa Kar
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Bioinformatics and Theoretical Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557845383

Antimicrobial resistance is a global health concern, and carbapenem-resistant Acinetobacter baumannii (CRAB) is recognized as a 'priority threat pathogen' for which no new alternate treatment is available. It causes high mortality among intensive care patients, primarily associated with hospital-acquired infections. There has been a lack of knowledge on the intracellular trafficking of bacteria inside the host, which creates difficulty in effective treatment development. Considering the heterogeneity of A.baumannii, this proposal formulated three objectives, which will increase the state-of-the-art knowledge of A.baumannii pathogenesis and provide an opportunity for new alternate treatment design. The proposal's first objective will focus on the comparative pathogenesis mechanism of A.baumannii in the presence or absence of antibiotic stress. Employment of differential gene expression analysis, regulatory network construction, and functional gene set enrichment analysis will provide a clear picture of underlying pathogenesis mechanisms by identifying up/down-regulated genes. Next, the key drug targets will be identified with the help of epitope profiling and analysis of regulatory networks established from the first objective. Based on the novel drug targets, the proposal aims to design an antibody-drug conjugate where bispecific antibodies bind with antigens as an alternate treatment. The drug/cytotoxic payload will be attached to the antibody using a linker, and as a choice of drug, both conventional antibiotic and antimicrobial peptides have been chosen. As the conjugates will target CRAB, a carbavance (carbapenem+vaborbactam) antibiotic has been chosen. The conjugates binding affinity and pharmacokinetic properties will be evaluated computationally, improving the chances of clinical success. Completing these objectives will deepen the understanding of A. baumannii pathogenesis and potentially lead to the development of novel, effective treatments to combat drug-resistant infections.

• DFG Programme: WBP Position