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Antimicrobial resistance is a growing threat, where bacteria develop ways to circumvent themechanisms of action of existing antibiotics. Thus, there is not only a need for newantimicrobials to see the light of day, but also drugs with novel mechanisms of action. The needis especially dire in the case of Gram-negative infections. A large reason for the lack oftreatments targeting Gram-negatives is the cell envelope characteristic to this type of pathogen,consisting of both an inner and an outer membrane. Hence, if the drug has an intracellular target,the compound must cross two membranes to carry out its effect. However, recent discoveriesoffer a glimmer of hope in the form of the LolCDE complex, a lipoprotein transporter that sitsin the inner membrane of the Gram-negative bacterium. Not only is inhibiting this structure aneffective way of targeting Gram-negatives, but it also erases the challenge of the drug moleculehaving to cross multiple membranes.

The aim of this degree project was therefore to synthesise novel LolCDE inhibitors, utilisingstructural elements from already reported inhibitors. The synthetic strategy involved furnishingan imidazole scaffold, which was then functionalised using palladium-catalysed CH-bondarylations. Functionalisations were proposed to explore initial structure-activity relationships.While three finished analogues could be made in quantities that would allow for identification,this was not the case for others, hence exposing room for improvement of the experimentalmethod. The three successfully synthesised analogues will be tested for antimicrobial activityby screening the molecules against a panel of wild-type E. coli as well as a TolC mutant strainto assess the effect of active efflux on the efficacy. The antimicrobial data is currently pending.