Evidence For Inhibition Of Topoisomerase 1A By Gold(Iii) Macrocycles And Chelates Targeting Mycobacterium Tuberculosis And Mycobacterium Abscessus

Keywords

Antibiotic; Drug discovery; Drug screening; Gold; Metallodrug; Mycobacterium; Mycobacterium abscessus; Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis. We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 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 M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus 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.

Publication Date

5-1-2018

Publication Title

Antimicrobial Agents and Chemotherapy

Volume

62

Issue

5

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1128/AAC.01696-17

Socpus ID

85046009511 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85046009511

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