ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents

Durcik, Martina; Tomašič, Tihomir; Zidar, Nace; Zega, Anamarija; Kikelj, D.; Mašič, Lucija Peterlin; Ilaš, Janez

doi:10.1080/13543776.2019.1575362

Cited by 50 publications

(55 citation statements)

References 37 publications

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“…NMR spectra ( 1 H and 13 C) were obtained on a Bruker AVANCE III spectrometer (Bruker Corporation. Billerica, MA, USA) at 400 and 100 MHz, respectively, in dimethyl sulfoxide (DMSO)-d 6 or CDCl 3 solution with tetramethylsilane as an internal standard. High-resolution mass spectra were obtained on Advion CMS (Advion Inc., Ithaca, USA) or VG Analytical Autospec Q mass spectrometer (Fisons, VG Analytical, Manchester, UK).…”

Section: Methodsmentioning

confidence: 99%

“…By introducing a p-chloro phenyl (4), IC 50 s in the low nanomolar range were achieved for S. aureus and eightfold lower MICs were observed on all three strains. The breakthrough was accomplished with p-bromo (5) and p-iodo phenyl (6) derivatives that show strong inhibitory activities against DNA gyrase from both organisms (S. aureus and E. coli). S. aureus DNA gyrase inhibitory potencies (IC 50 of 0.007 μM for 5 and 0.011 μM for 6, respectively) are the most potent reported to date for an NBTI.…”

Section: Design Of Nbtis With the Focus On The Rhs As Presented Inmentioning

confidence: 99%

“…DNA gyrase consists of two copies of GyrA (which contains the catalytic tyrosine) and two copies of GyrB (which comprises the ATPase activity) thus functioning as an A 2 B 2 heterotetramer 4 . The A 2 B 2 heterotetramer can accommodate a variety of inhibitors that prevent DNA gyrase function, namely, the catalytic inhibitors and cleavage-complex stabilizers [5][6][7][8] . Among the recently discovered compounds, the novel bacterial type II topoisomerase inhibitors (NBTIs) are probably the closest to clinical use 9 .…”

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confidence: 99%

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Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds

Kolarič,

Germe,

Hrast

et al. 2021

Nat Commun

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Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase–DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.

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Section: Methodsmentioning

confidence: 99%

Section: Design Of Nbtis With the Focus On The Rhs As Presented Inmentioning

confidence: 99%

mentioning

confidence: 99%

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Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds

Kolarič,

Germe,

Hrast

et al. 2021

Nat Commun

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“…is the main mechanism of P. aeruginosa's resistance to β-lactams [19]. Fluoroquinolones inhibit DNA gyrase (subunit composition: gyrA and gyrB) and topoisomerase IV (subunit composition: parC and parE) of bacteria [20], but the mutation of any these subunits leads to the resistance of bacteria to fluoroquinolones. As such, we chose to explore the combination of levofloxacin and ceftazidime.…”

Section: Discussionmentioning

confidence: 99%

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

Jian

2020

BMC Pharmacol Toxicol

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Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as both monotherapy and combination therapy, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16-20 mL/min) renal function. Common clinical administration regimens to provide reference values were further evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853), which simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. Total and resistant populations were quantified. Drug concentrations were determined by high-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8 h, whilst combination regimens resulted in 2-to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6 h, and was seen at 0 h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0 h, there was a definite downward trend after 8 h, while resistant population in the normal renal function group increased after 16 h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.

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“…is the main mechanism of PA's resistance to βlactams (18). Fluoroquinolones inhibit DNA gyrase (subunit composition: gyrA and gyrB) and topoisomerase IV (subunit composition: parC and parE) of bacteria (19), but the mutation of any these subunits leads to the resistance of bacteria to fluoroquinolones. As such, we chose to explore the common combination of levofloxacin and ceftazidime, and this study is the first to use a HFIM to investigate the effects of the two drugs on bacterial kill and inhibition of resistance emergence in patients with abnormal renal function.…”

Section: Discussionmentioning

confidence: 99%

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

He²,

Jian

2020

Preprint

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Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as monotherapy and in combination, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16–20 mL/min) renal function. Common clinical administration regimens to provide reference values were also evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853). This simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. The total and resistant populations were quantified. Drug concentrations were determined by High-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8h, whilst combination regimens resulted in 2- to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6h, and was seen at 0h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0h, there was a certain downward trend after 8h, while resistant population in the normal renal function group increased after 16h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.

show abstract

ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents

Cited by 50 publications

References 37 publications

Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds

Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

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