The antimicrobial mode of action of tropolone: selective metal chelation and targeted inhibition of metalloenzymes

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Tropolone and its derivatives possess non-benzenoid, 7-carbon ring structures and have long been recognised as potent antibacterial and antifungal agents. Recent studies have revealed that they can function as specific inhibitors of a variety of metalloenzymes, including tyrosinases, elastases, epimerases and enolases, where they associate with the metal cation at the enzyme active site to disrupt functionality. However, in several cases the enzymes recognised by tropolone are not essential suggesting that multiple metalloenzymes may be targeted in a similar fashion. Details on which molecular pathways are disrupted by these compounds remain unclear. Tropolone also has the ability to function as a metal chelator and the contribution of this factor to antimicrobial activity has yet to be explored. Preliminary studies have revealed differing effects of tropolone and the closely related compound, hinokitiol (b-thujaplicin), on cellular metal levels in bacteria. These results suggest that there may well be differences in the mode of action of different tropolones and further work is needed to define precisely their metalloenzyme targets, the metabolic pathways affected and the contribution of metal deprivation to antimicrobial activity. Tropolones are highly effective against species that are notoriously difficult to eliminate, such as the bacterium Serratia marcescens and the fungus Candida albicans. Both organisms are notable opportunistic human pathogens, so in addition to benefits for industrial applications, a better understanding of the multifunctionality of tropolone will also inform its potential as a new antimicrobial agent to combat infections. This project aims to determine the antimicrobial mode of action of tropolone against S. marcescens and C. albicans and evaluate its activity in tandem with chelants routinely employed in P&G products. Information uncovered on the mode of action by restriction of metal availability or by specific effects on metalloenzymes will allow the development of improved formulations and offer insight into how metal handling can be disrupted to boost antimicrobial efficacy.