The novel anti-infective BDM-I : clinical utility and mechanism of action

Western Sydney University thesis: Doctoral thesis

Abstract

Since the introduction of antibiotics into clinical use, bacteria have continued to evolve and acquire mechanisms of resistance. In a relatively short time period, this has rapidly escalated into a serious health crisis recognised by major governing/scientific bodies worldwide. The rate at which antibiotic resistance spreads now outpaces our current ability to discover and manufacture new antibiotics. Steps taken to combat antibiotic resistance have had little impact in preventing the spread of relevant pathogens, especially within hospital settings. The current state of antibiotic development has only exacerbated these issues by severely limiting the arsenal of therapeutics available to treat problematic infections. Without sufficient incentives, large pharmaceutical companies have focused on developing financially 'safe' drugs to treat non-infectious related conditions, leaving the bulk of antibiotic research to smaller biotechnology companies and academia, often in collaboration together. In this study, we have examined the clinical utility and mechanism of action (MoA) of BDM-I, which is a small synthetic molecule currently being developed by the Australian biotechnology company Opal Biosciences Limited. Importantly, BDM-I (3,4- methylenedioxy-B-nitropropene) appears to be a novel antimicrobial compound and has shown promising activity in vitro against clinically relevant pathogens, such as MRSA and VRE. In this regard, previous studies have shown that BDM-I does not inhibit common antimicrobial targets, and proposed that it binds to bacterial tyrosine phosphatases. While an antibiotic inhibiting a novel cellular target(s) is desirable, in this case the specific MoA (of BDM-I) and its physiological effect on bacterial cells is not known, thus limiting the potential for further development. Therefore, due to this knowledge gap, we attempted to gain insight into the BDM-I MoA (including its binding partner) using an omics approach (i.e. whole genome sequencing and proteomics). Additionally, we also aimed to study the activity of BDM-I against the clinically relevant ESKAPE pathogens.
Date of Award2019
Original languageEnglish

Keywords

  • antibiotics
  • therapeutic use
  • genomics
  • proteomics
  • drug resistance in microorganisms

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