The overview of development of novel bacterial topoisomerase inhibitors effective against multidrug-resistant bacteria in an academic environment: from early hits to in vivo active antibacterials

This article reviews our efforts in developing highly potent NBTIs over the past decade. Following the discovery of an initial hit with potent enzyme inhibitory and broad-spectrum antibacterial activity, an extensive hit-to-lead campaign was conducted with the goal of optimizing physicochemical properties, reducing hERG inhibition, and maintaining antibacterial activity against both Gram-positive and Gram-negative bacteria, with a focus on methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy resulted in an amide-containing, focused NBTI library with compounds exhibiting potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in in vivo zebrafish model, and favorable in vivo efficacy in a neutropenic murine thigh infection model for MRSA infections.PMID:37949194 | DOI:10.1016/j.ejps.2023.106632

Source: European Journal of Pharmaceutical Sciences - November 10, 2023 Category: Drugs & Pharmacology Authors: Ma ša Zorman Martina Hrast Maja Kokot Nikola Minovski Marko Anderluh Source Type: research