Non-quinolone Inhibitors of Bacterial Type IIA Topoisomerases: A Feat of Bioisosterism

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

“…Notably, several antimicrobials or other compounds, using new targets or mechanisms, were recently developed, and several have shown high in vitro activities against gonococcal isolates. These include novel inhibitors of protein synthesis, e.g., pleuromutilin BC-3781 (318,319) and the boron-containing inhibitor AN3365 (320,321); novel inhibitors of bacterial topoisomerases that target regions different from the fluoroquinolone-binding sites (322,323), such as VT12-008911 (324) and AZD0914 (323,325,326); FabI inhibitors, such as MUT056399 (327,328); noncytotoxic nanomaterials (329); inhibitors of efflux pumps, particularly coadministered with appropriate antimicrobials, that increase the susceptibility to certain antimicrobials, the innate host defense, and toxic metabolites (234,260,330); LpxC inhibitors (331); molecules mimicking host defensins; host defense peptides, such as LL-37 (multifunctional cathelicidin peptide) (332); and IL-12 NanoCap, which is a biodegradable sustained-release formulation of human interleukin 12 that aims to be a therapeutic vaccine against N. gonorrhoeae (TherapyX Inc.). Several of these novel antimicrobials or other types of compounds deserve further attention for their potential use as future treatments for gonorrhea.…”

Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

“…3 Several novel (nonfluoroquinolone) bacterial type II topoisomerase inhibitors (NBTIs) have been recently described. 4 These inhibitors bind to different sites of gyrase A and ParC and generally do not show cross-resistance to fluoroquinolones. 5−15 The alternative-binding site of these inhibitors was demonstrated by the X-ray crystal structure of one of the inhibitors (GSK299423, 3) bound to DNA-bound gyrase complex of S. aureus.…”

High In Vitro Susceptibility to the Novel Spiropyrimidinetrione ETX0914 (AZD0914) among 873 Contemporary Clinical Neisseria gonorrhoeae Isolates from 21 European Countries from 2012 to 2014

“…These action/response plans strongly emphasize the necessity of novel antimicrobials or other therapeutic compounds for effective treatment of gonorrhea. The spiropyrimidinetriones comprise a newly developed class of antimicrobials that act via a new drug target and novel DNA topoisomerase II (DNA gyrase/topoisomerase IV) inhibitor mode of inhibition, which differs from the mode of action of all currently licensed antimicrobials, including other DNA topoisomerase II inhibitors such as the fluoroquinolones (19,20). ETX0914 (also known as AZD0914) is a novel, not yet commercially available or clinically used, spiropyrimidinetrione that inhibits bacterial DNA topoisomerase II.…”

“…ETX0914 (also known as AZD0914) is a novel, not yet commercially available or clinically used, spiropyrimidinetrione that inhibits bacterial DNA topoisomerase II. Accordingly, ETX0914 inhibits the DNA biosynthesis and replication by an accumulation of DNA double-strand cleavages and, in contrast to fluoroquinolones, prevention of religation, resulting in a bactericidal activity (19)(20)(21). ETX0914 has been shown to have a high in vitro activity against many different bacterial species, including Gram-positive, Gram-negative, and anaerobic isolates (19).…”