Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2024

Antimicrobial resistance (AMR) poses a significant threat to global health, necessitating novel strategies to address multi-drug and extensively-drug resistant bacteria. Moreover, there is a dearth of antibiotics in the clinical pipeline with only two new antibiotic classes being approved more than a decade ago – neither possessing broad-spectrum activity. AMR is attributed to anthropogenic use and misuse of antibiotics, intrinsic bacterial resistance mechanisms, and resistance gene transmission between bacteria. Additionally, most pathogenic bacterial species form biofilms – a community of homo- or heterogenous microorganisms encased in an array of extracellular polymeric substances. These aggregates facilitate resistance gene transfer and impede antibiotic diffusion, ultimately acting as a protective barrier and furthering AMR. Consequently, there is an urgent need for novel antibacterial agents, including ones that can target and eradicate biofilms. One strategy to address the issues of AMR and biofilms is the development of antibiotic hybrids, defined herein as the conjugation of an antibiotic to an antibiofilm moiety. The project presented here aims to develop dual-acting compounds to target and eradicate biofilms, through antibiotic-antibiofilm hybrids. Selection of the antibiofilm moiety was inspired by the antibiofilm activity of permanently ionized quaternary atoms (i.e., ammonium) covalently bonded to antibiotics. Our approach to hybrid development involves installation of readily derivatisable chemical handles to antibiotics, which are then linked to the antibiofilm component using ‘click’ chemistry. This ‘click’ approach allows for the rapid synthesis of hybrids and to investigate the activity of various antibiotic classes when conjugated to an antibiofilm agent. Novel hybrids are then tested to assess activity against various Gram-negative and -positive bacteria, and biofilms for minimum biofilm eradication concentration (MBEC).Thus far, several hybrids have shown promising and biofilm work is ongoing. If successful, these dual-acting compounds have the potential to advance the management of chronic infections caused by these bacterial communities and restock the antibiotic pipeline.