In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

Abstract

dOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16-to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.

Antibacterial activity of novel dual bacterial DNA type II topoisomerase inhibitors

“…At higher concentrations, the frequency of resistance was less than 1×10 −8 for all compounds and comparable to ciprofloxacin. These data suggest a low potential for resistance development for the compounds in line with the balanced dual-targeting activity and are in agreement with recently published data describing new NBTIs [45,[56][57][58]. Tam et al [56] generated S. aureus ATCC 29213 mutants that were resistant (mutation frequency of 3×10 −6 ) to the compound AZD5206 at 3× MIC.…”

“…Tam et al [56] generated S. aureus ATCC 29213 mutants that were resistant (mutation frequency of 3×10 −6 ) to the compound AZD5206 at 3× MIC. Similarly, the NBTI compounds described by Lahiri et al [45] and by Tan et al [58] showed mutation frequencies of 1.7×10 −8 and 6.7×10 −7 at concentrations of 4× MIC. For Gram-negative strains, a mutation rate of 1.8×10 −7 was reported in P. aeruginosa exposed to NBTI-5463 at 2× MIC [57].…”

Antioxidant, Anti-Lung Cancer, and Anti-Bacterial Activities of Toxicodendron vernicifluum

“…There are several research findings which indicate the application of the NBTIs on the development of novel antibacterial agents [25,26,27]. It is also reported that targeting the NBTIs is an auspicious approach for the development of resistant strain of Staphylococcus aureus (MRSA) [28]. Moreover, the protein penicillin-binding protein 2a (PBP2a) in MRSA enhanced resistance on β-lactams or other antibiotics.…”

Identification and characterization of potential membrane-bound molecular drug targets of methicillin-resistant Staphylococcus aureus using in silico approaches

“…Today, a number of proteins are considered as promising drug targets for the development of antibiotics to treat staphylococcal infections. After extensive review of the literature for the last three years, the following proteins were considered as potential therapeutic drug targets for the development of antistaphylococcal agents: bacterial enoyl reductase (FabI) [3,4], transglycosylase (TGase) [5,6], sortase A [7][8][9][10][11][12][13], diapophytoene desaturase (CrtN) [14][15][16][17], type II topoisomerase [18][19][20][21], topoisomerase IV [22][23][24][25][26][27], filamentous temperature-sensitive protein Z (FtsZ) [28][29][30], UDP-N-acetylenolpyruvylglucosamine reductase (MurB) [31], lipoteichoic acid synthase (LtaS) [32], biotin protein ligase [33,34], peptide deformylase [35], Ser/Thr protein kinase STK1 [36], pentaerythritol tetranintrate reductase [37], peptide deformylase (PDF) [38,39], NorA efflux pump [40][41][42][43][44]…”