Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus

Abstract

and the fast-growing species are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant strains and the high level of intrinsic resistance of 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 and We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating 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 and 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 gyrase. 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 and 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.

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…Compound 29 , in particular, showed excellent promise, with encouraging phenotypic activity against both Mtb and M. abscesses , which was maintained against several clinically isolated strains. Furthermore, this study found compelling evidence that compound 29 exerts its effect via selective inhibition of topoisomerase type I …”

“…Following a study by Akerman et al. which identified a cohort of gold(III) complexes as site‐specific catalytic inhibitors of human topoisomerase IB and given the potential of type I topoisomerases as targets in mycobacteria, Rohde and co‐workers assessed this class of compounds as potential leads for anti‐mycobacterial drug discovery . Compound 29 , in particular, showed excellent promise, with encouraging phenotypic activity against both Mtb and M. abscesses , which was maintained against several clinically isolated strains.…”

Type IA Topoisomerases as Targets for Infectious Disease Treatments

“…Gold(III) macrocycle 10 had even lower MICs against the mycobacteria but was not bactericidal, so these two compounds may have differences in their mechanism of action. Gold(III) chelate 14 showed no activity against Gram-negative species and only low level inhibition against other Gram-positives, suggesting that it has a specific activity against mycobacteria, including fluoroquinolone-resistant strains [ 113 ]. Both compounds shown in Figure 5 inhibit the relaxation activity of M. tuberculosis and E. coli topoisomerase I ( Table 1 ), without any effect on bacterial DNA gyrase activity, suggesting the specificity these two compounds have for bacterial type IA topoisomerases inhibition [ 113 ].…”

“…Gold(III) chelate 14 showed no activity against Gram-negative species and only low level inhibition against other Gram-positives, suggesting that it has a specific activity against mycobacteria, including fluoroquinolone-resistant strains [ 113 ]. Both compounds shown in Figure 5 inhibit the relaxation activity of M. tuberculosis and E. coli topoisomerase I ( Table 1 ), without any effect on bacterial DNA gyrase activity, suggesting the specificity these two compounds have for bacterial type IA topoisomerases inhibition [ 113 ]. Further studies are required to characterize the mechanism of antimycobacterial action of these gold(III) compounds and provide more insights in their structure–activity relationship (SAR) to limit the cytotoxicity.…”

“… Gold(III) inhibitors of bacterial topoisomerase I [ 113 ]. ( A ) Gold(III) macrocycle 10 and ( B ) gold(III) chelate 14.…”