Honours Project: Klementine Burrell Sander

Abstract

Tuberculosis (TB) is the leading cause of death by a single infectious agent. While drug-susceptible TB responds well to current treatments, increasing rates of drug-resistant TB (DR-TB) necessitate the development of novel antitubercular agents that can act via new mechanisms to treat patients with DR-TB. The development of such drugs has been the focus of an open-source drug discovery (OSDD) initiative known as Open-Source Tuberculosis (OSTB). OSDD projects seek to design and develop drugs following the principles of open science, meaning that all research is transparent, openly accessible and collaborative.

The Rutledge and Todd groups at the University of Sydney have previously identified cyclam-based compounds with hydrophobic pendants as having good antitubercular without being toxic to human cells REF. Additionally, recent work from the Rutledge group has indicated that linear polyamine compounds with the same hydrophobic pendants also exhibit promising antitubercular activity. These compounds form the basis of Series 4 of the OSTB consortium.

The current research investigates the effect of new hydrophobic pendant groups appended to the cyclam core and implements a diversity-oriented synthesis (DOS) scheme to examine structure-activity relationships (SAR) in the linear polyamine compounds. DOS is a strategy for rapidly creating libraries of structurally diverse bioactive compounds. In addition, the activity of OSDD projects on the social network Twitter has been studied to determine how OSDD work can reach a wider audience of potential new collaborators. Social network analysis (SNA) enabled the assessment of current OSDD initiatives over time and in response to the implementation of strategies designed to broaden and improve the relevant networks.

Numerous transformations including acylation, allylation, and propargylation were attempted on a linear diaminohexane scaffold, with varying success. Progress was made towards installing ferrocenyl groups on a cyclam core, and a cyclam-based compound with adamantyl pendants showed good antitubercular activity when assessed in vivo using a resazurin assay.

Study of the OSDD networks revealed that the projects are largely not achieving their goals of reaching a broad, diverse audience, in part due to ineffective use of communication strategies. While deliberate content mediation did improve engagement and reach for the OSTB project, it is recommended that each project clearly establish communication goals and use evidence-based strategies of content mediation to achieve these goals.