Novel macrozone-based two-site ribosome inhibitors: Design, synthesis and interactions; HrZZ IP-2026-5127

Obrisani Korisnik — Thu, 08 Oct 2026 10:03:09 GMT

Abstract

Antimicrobial resistance (AMR) presents a serious threat to human health worldwide by dramatically reducing our ability to treat infections effectively. AMR causes millions of deaths annually and this number is expected to rise unless new anti-infective agents are developed.Consequently, combating the AMR has become a critical global health priority and considerable research efforts are focused on the discovery of novel, safe and effective drugs active against resistant bacterial pathogens. This challenge is further intensified by a lack of innovation in the antibiotic pipeline, underscoring the urgent need for the discovery and development of new antibiotics to tackle AMR.

Hence, the main objective of the proposed project is design, preparation, biological evaluation and molecular interactions of a new class of bioactive azithromycin conjugates. We plan to prepare a library of novel 4”-azithromycin conjugates, macrolozones by varying the linker length and by further introducing aromatic moieties in the azithromycin scaffold to increase lipophilic properties and the number of hydrogen bonds and positively charged centers. This can be crucial for optimizing two-site binding to bacterial ribosomes and also for enhancing bacterial cell up-take. Based on the results of our previous project, which highlighted hydrogen bond interactions and pi-electron delocalization as crucial for antibacterial activity of azithromycin conjugates, the main focus in this project will be on novel multiple-site inhibitors of resistant S. aureus, S. pneumoniae, S. pyogenes and E. coli strains being among those of highest public health importance. Our preliminary docking studies have indicated that by elongation of the linker length the thiosemicarbazone part can immerse deeper into the bacterial ribosome, forming additional interactions that strengthen the overall binding. We believe that expertise and knowledge of the project team and proposed methods and resources will enable a discovery of novel and more potent macrolozones active against sensitive and resistant bacteria thus advancing global human health.

Project leader: Prof. Predrag Novak

Collaborators: Assoc. Prof. Tomislav Jednačak; Iva Habinovec, senior expert associate; Katarina Pičuljan, expert; Assoc. Prof. Đani Škalamera; Mirjana Bukvić, senior researcher; Jelena Parlov Vuković, research associate; Hana Čipčić Paljetak, senior research associate; Assoc. Prof. Klaus Zangger; Prof. Branimir Bertoša, consultant

Scheme 1. Representative series of novel macrolozones.

Scheme 2. Work packages for the project.

PMF - HRZZ_Novak

Novel macrozone-based two-site ribosome inhibitors: Design, synthesis and interactions; HrZZ IP-2026-5127