Combatting antimicrobial resistance: Small-molecule inhibitors as precision anti-virulence agents

Ralif, Laila (2023) Combatting antimicrobial resistance: Small-molecule inhibitors as precision anti-virulence agents. Masters by Research thesis (MPhil), Manchester Metropolitan University.

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Abstract

Antimicrobial resistance (AMR) is an ever-increasing global problem and it is estimated that deaths associated with AMR infections will exceed 10 million by 2050, superseding cancer as the leading cause of global mortality. Traditional antibiotics display antimicrobial activity through direct targeting of key bacterial cellular processes such as cell wall formation, which are essential for viability but are susceptible to resistance generation. In contrast, one approach to combating AMR is the development of novel small-molecule inhibitors (SMIs) as anti-virulence agents, which target pathogen specific virulence-related traits, such as enzymes involved in the generation of post-translational modifications, biofilm formation and toxin production. This study aimed to determine the anti-virulence activity of a novel library of SMIs designed for precision targeting of essential epigenetic bacterial targets. Antimicrobial susceptibility and time-kill kinetic assays identified four lead candidates which demonstrated activity against methicillin-resistant Staphylococcus aureus (MRSA). One lead SMI was able to resolve MRSA infections in the Galleria mellonella in vivo model, with no observed cytotoxicity being exhibited within the larvae. Research is now focused on determining the downstream effects of these SMIs on MRSA virulence traits, such as biofilm formation and quorum sensing, in addition to confirming the bacterial cellular target site via affinity chromatography coupled with determining binding affinity. This research represented a significant advance in the search for novel antimicrobial agents which target essential bacterial processes beyond those associated with traditional antibiotics.