Gold(III) macrocycles and chelates targeting Mycobacterium tuberculosis and Mycobacterium abscessus: evidence for inhibition of topoisomerase 1A [PublishAheadOfPrint]

Mycobacterium tuberculosis (Mtb) and the fast-growing Mycobacterium abscessus (Mab) are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug resistant Mtb strains and the high level of intrinsic resistance of Mab calls for novel drug scaffolds that effectively target both pathogens. In this study, we have evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase I and II, against Mab and Mtb. We identified a total of 5 non-cytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse Mtb and Mab clinical isolates. Prompted by previous data suggesting that 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the Mtb gyrase. In vitro enzyme assays confirmed potent activity against bacterial topoisomerase IA (Topo1) enzymes, but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against Mtb and Mab that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

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