FtsZ inhibitors as a new genera of antibacterial agents

Tripathy, Swayansiddha; Sahu, Susanta Kumar

doi:10.1016/j.bioorg.2019.103169

Cited by 73 publications

(55 citation statements)

References 117 publications

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“…During the first treatment with C109, 70% of the cells slowly decreased their rate of growth and division ( Figures 5, 6B, 7B), increasing their area of 2-fold, and then died by lysis (Figures 5, 7C). These results were expected and consistent with previous observations upon inhibition of an essential component of the cell divisome by treatment with C109, and in case of other FtsZ inhibitors (Scoffone et al, 2015;Hogan et al, 2018;Tripathy and Sahu, 2019). The lytic phenotype could be explained because FtsZ is an essential component of the cell divisome and controls the cell wall biosynthesis at the septum site (Yang et al, 2017).…”

Section: Time-lapse Microscopy Of B Cenocepacia Treated With C109 Resupporting

confidence: 92%

Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia

et al. 2020

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There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.

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Section: Time-lapse Microscopy Of B Cenocepacia Treated With C109 Resupporting

confidence: 92%

Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia

et al. 2020

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“…The two in vitro assays are the ones widely used to investigate changes in FtsZ enzymatic function, as suggested by Kusuma and Tripathy in recent reviews on this topic. [30,31] FtsZ inhibition of PC190723 and of other FtsZ inhibitors was confirmed in this way.…”

Section: Introductionsupporting

confidence: 69%

“…Besides, we confirmed FtsZ as the target of this class of derivatives using a GTPase activity assay and a polymerization activity assay. The two in vitro assays are the ones widely used to investigate changes in FtsZ enzymatic function, as suggested by Kusuma and Tripathy in recent reviews on this topic . FtsZ inhibition of PC190723 and of other FtsZ inhibitors was confirmed in this way.…”

Section: Introductionmentioning

confidence: 63%

Benzodioxane‐Benzamides as Antibacterial Agents: Computational and SAR Studies to Evaluate the Influence of the 7‐Substitution in FtsZ Interaction

et al. 2019

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FtsZ is a crucial prokaryotic protein involved in bacterial cell replication. It recently arose as a promising target in the search for antimicrobial agents able to fight antimicrobial resistance. In this work, going on with our structure‐activity relationship (SAR) study, we developed variously 7‐substituted 1,4‐benzodioxane compounds, linked to the 2,6‐difluorobenzamide by a methylenoxy bridge. Compounds exhibit promising antibacterial activities not only against multidrug‐resistant Staphylococcus aureus, but also on mutated Escherichia coli strains, thus enlarging their spectrum of action toward Gram‐negative bacteria as well. Computational studies elucidated, through a validated FtsZ binding protocol, the structural features of new promising derivatives as FtsZ inhibitors.

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“…Inhibition of FtsZ has a bactericidal rather than bacteriostatic effect 8,11 , a property that reduces the potential for emergence of future resistance 18 . FtsZ also has no functional human homolog, offering the potential to target this protein specifically and with minimal toxicity 12,19 . It is one of the most abundant and highly conserved cytoskeleton proteins among eubacteria 20 , offering FtsZ inhibitors the potential for broad-spectrum antibacterial activity.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Design of a Fluorescent Probe for the Visualization of FtsZ in Clinically Important Gram-Positive and Gram-Negative Bacterial Pathogens

Ferrer-González

Fujita

Yoshizawa

et al. 2019

Sci Rep

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Addressing the growing problem of antibiotic resistance requires the development of new drugs with novel antibacterial targets. FtsZ has been identified as an appealing new target for antibacterial agents. Here, we describe the structure-guided design of a new fluorescent probe (BOFP) in which a BODIPY fluorophore has been conjugated to an oxazole-benzamide FtsZ inhibitor. Crystallographic studies have enabled us to identify the optimal position for tethering the fluorophore that facilitates the high-affinity FtsZ binding of BOFP. Fluorescence anisotropy studies demonstrate that BOFP binds the FtsZ proteins from the Gram-positive pathogens Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae with Kd values of 0.6–4.6 µM. Significantly, BOFP binds the FtsZ proteins from the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii with an even higher affinity (Kd = 0.2–0.8 µM). Fluorescence microscopy studies reveal that BOFP can effectively label FtsZ in all the above Gram-positive and Gram-negative pathogens. In addition, BOFP is effective at monitoring the impact of non-fluorescent inhibitors on FtsZ localization in these target pathogens. Viewed as a whole, our results highlight the utility of BOFP as a powerful tool for identifying new broad-spectrum FtsZ inhibitors and understanding their mechanisms of action.

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FtsZ inhibitors as a new genera of antibacterial agents

Cited by 73 publications

References 117 publications

Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia

Chemical, Metabolic, and Cellular Characterization of a FtsZ Inhibitor Effective Against Burkholderia cenocepacia

Benzodioxane‐Benzamides as Antibacterial Agents: Computational and SAR Studies to Evaluate the Influence of the 7‐Substitution in FtsZ Interaction

Structure-Guided Design of a Fluorescent Probe for the Visualization of FtsZ in Clinically Important Gram-Positive and Gram-Negative Bacterial Pathogens

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