Rapidly accessible divalent LecA inhibitors targeting biofilm formation of Pseudomonas aeruginosa
Dr Alexander Titz, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Eva Zahorska, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Saverio Minervini , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); Dr Anne Imberty, Université Grenoble Alpes, CNRS, CERMAV; Dr Sakonwan Kuhaudomlarp, Université Grenoble Alpes, CNRS, CERMAV
Gram-negative bacteria Pseudomonas aeruginosa is responsible for a wide-range of nosocomial infections, particularly in immunocompromised patients. It has been classified as priority 1 pathogen by WHO since 2017 due to its high antimicrobial resistance. Alternative treatment strategies are urgently needed. The anti-virulence therapy is a treatment strategy focusing on neutralization of bacterial virulence factors instead of targeting essential cellular functions. D-galactose specific lectin LecA is a virulence factor that plays a key role in adhesion and biofilm formation, thus it is recognized as a new therapeutic target. Weak affinity of known monovalent LecA inhibitors (micromolar range) can be improved with increasing valency by several orders of magnitude (low nanomolar range). However, multivalent inhibitors are not suitable for drug development due to their complexity, lack of synthetic accessibility and drug like properties.
We designed divalent LecA inhibitors with focus on drug-like properties and synthetic accessibility, enabling future lead optimization. Low nanomolar LecA inhibitors were synthesized in simple four chemical steps. Length and flexibility of divalent LecA inhibitors was varied to optimize binding to neighboring binding sites within one LecA tetramer and avoid unwanted cross-linking. Our design of divalent LecA inhibitors is suitable for medicinal chemistry optimization with easy modular replacement of the aglycone and linking unit. Solubility optimization produced the lead compound with excellent solubility in buffer (above 1.5 mM) and retained activity on the target. Furthermore, we modified the linking unit for click chemistry in order to attach imaging moieties for diagnostic purposes.
New antiinfective against chronic lung infections in cystic fibrosis and ventilator associated pneumonia and against chronic skin infections with P. aeruginosa. Use as antibiotic adjuvant preferred.
Project is in hit to lead optimization phase. Data from several in-vitro binding assay are available. Cell-based assays are ongoing and experiments in a suitable in vivo infection model are in preparation.
A patent has been filed in November 2019 (EP19306432.6).
 S. Wagner, R. Sommer, S. Hinsberger, C. Lu, R. W. Hartmann, M. Empting, A. Titz, J. Med. Chem. 2016, 59, 5929–5969.
 E. Zahorska, S. Kuhaudomlarp, S. Minervini, S. Yousaf, M. Lepsik, T. Kinsinger, A. K. H. Hirsch, A. Imberty, A. Titz, Chem. Commun. 2020, 56, 8822–8825.