The Structural Features of Novel Bacterial Topoisomerase Inhibitors That Define Their Activity on Topoisomerase IV

Abstract

The continued emergence of bacterial resistance has created an urgent need for new and effective antibacterial agents. Bacterial type II topoisomerases, such as DNA gyrase and topoisomerase IV (topoIV), are well-validated targets for antibacterial chemotherapy. The novel bacterial topoisomerase inhibitors (NBTIs) represent one of the new promising classes of antibacterial agents. They can inhibit both of these bacterial targets; however, their potencies differ on the targets among species, making topoIV probably a primary target of NBTIs in Gram-negative bacteria. Therefore, it is important to gain an insight into the NBTIs key structural features that govern the topoIV inhibition. However, in Gram-positive bacteria, topoIV is also a significant target for achieving dual-targeting, which in turn contributes to avoiding bacterial resistance caused by single-target mutations. In this perspective, we address the structure–activity relationship guidelines for NBTIs that target the topoIV enzyme in Gram-positive and Gram-negative bacteria.

Diminishing hERG inhibitory activity of aminopiperidine-naphthyridine linked NBTI antibacterials by structural and physicochemical optimizations

“…This suggests that a diminished hERG inhibition of the aminopiperidine linked NBTIs could be achieved by removing the piperidine tertiary amine, which does not interact with the enzyme nor the DNA. This is in line with the well-established SAR guidelines for LHS and RHS fragments [16,17,38]. Consequently, we designed a new, optimized series of NBTIs by retaining the identical LHS and RHS fragments, and by substituting the piperidine linker moiety with cyclohexane and tetrahydropyran linkers to omit the tertiary amine (Fig.…”

“…The hERG IC 50 values of compounds 4-18 are summarized in Table 3. Compared to the aminopiperidine-naphthyridine linked NBTIs from our previous study (1-3 in Table 3 and S1-S25 in Supporting Information, Table S1) [39], the newly optimized NBTIs (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) show at least one order of magnitude weaker inhibition of the hERG potassium channel. As demonstrated in Table 3, the removal of the basic tertiary amine results in less potent inhibition of the hERG potassium channel for this series of NBTIs (1 compared to 5 and 11; 2 compared to 7, 13, and 17; and 3 compared to 9, 15, and 18).…”

“…In our previous studies, we improved the antibacterial activity of our series of aminopiperidine-naphthyridine linked NBTIs comprising phalogenated phenyl RHS fragments by strengthening the halogenbonding propensity on the enzyme binding side [17,38,39]. Indeed, this structural optimization yielded NBTIs with excellent antibacterial activities and enzyme inhibitory potencies, but with notable hERG inhibition that remains a major issue.…”

“…As demonstrated in Table 1 the structurally optimized NBTIs exhibit strong enzyme inhibitory activity in nanomolar concentrations for S. aureus and E. coli DNA gyrase as well as E. coli topoIV, however the majority of them show weaker inhibition against S. aureus topoIV relative to their predecessors (1-3). However, this is not detrimental, since the primary target of NBTIs in S. aureus is DNA gyrase, while in E. coli is most probably topoIV [17], which in turn means that the loss of inhibition of topoIV in S. aureus does not significantly affect the antibacterial activity and spectrum.…”

“…The NBTIs specific structure allows formation of a ternary complex with the enzyme and the DNA; namely, the left hand side (LHS) moiety intercalates between the central DNA base pairs, the right hand side (RHS) fragment binds into a deep, non-catalytic, hydrophobic binding pocket formed at the interface of both catalytic subunits, and a linker moiety connecting both parts (Fig. 1) [16,17]. Gepotidacin (GSK2140944), the most advanced representative of the NBTI's class of antibacterials is currently in the Phase 3 clinical trials for the treatment of uncomplicated urogenital gonorrhea caused by N. gonorrhoeae [18,19] as well as uncomplicated urinary tract infection (e.g., acute cystitis) most commonly caused by Escherichia coli [20][21][22].…”