Targeting FtsZ for Antituberculosis Drug Discovery:  Noncytotoxic Taxanes as Novel Antituberculosis Agents

Huang, Qing; Kirikae, Fumiko; Kirikae, Teruo; Pepe, Antonella; Amin, Amol; Respicio, Laurel; Slayden, Richard A.; Tonge, Peter J.; Ojima, Iwao

doi:10.1021/jm050920y

Cited by 102 publications

(95 citation statements)

References 11 publications

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“…Nevertheless, as we demonstrated in this work, concentrations within the soluble range of these drugs inhibited the growth of M. tuberculosis. It is well established in other organisms and in M. tuberculosis that inhibition of FtsZ leads to smooth filamentous cells while, in contrast, inhibition of FtsI produces filamentous cells with distinct septi Huang et al, 2006;Pogliano et al, 1997;Romberg & Levin, 2003). Analysis of M. tuberculosis treated with the benzimidazole compounds (FtsZ inhibitors) or known FtsI inhibitors (cephalexin and piperacillin) revealed cellular morphologies fully consistent with observations in other bacteria (Romberg & Levin, 2003).…”

Section: Discussionsupporting

confidence: 73%

“…3A-D) and this was consistent with the inhibition of Z-ring formation Huang et al, 2006). As a control, M. tuberculosis cultures were also treated with 20 mM cephalexin and 40 mM piperacillin, two known inhibitors of FtsI (Pogliano et al, 1997).…”

Section: Effect Of Ftsz Inhibition On Bacterial Viability and Cell Mosupporting

confidence: 76%

“…Based on the ability of benzimidazole and structurally related compounds to inhibit the GTPase activity of the M. tuberculosis FtsZ we hypothesized that albendazole and thiabendazole inhibit septum formation (Huang et al, 2006;Margalit et al, 2004). The MICs for albendazole and thiabendazole as determined by the microbroth dilution assay (Slayden et al, 2000) were found to be 60-120 mM and 80-160 mM, respectively.…”

Section: Effect Of Ftsz Inhibition On Bacterial Viability and Cell Momentioning

confidence: 99%

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Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis

2006

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In Mycobacterium tuberculosis the mechanism of septum formation and regulation of cell division remains undefined. In other bacterial species FtsZ polymerization and septum formation are influenced through protein interactions in addition to transcriptional regulation, and the combination of these provides tight regulation of this process. However, homologues of proteins known to affect FtsZ assembly have not been identified and substantiated in M. tuberculosis. This suggests that M. tuberculosis may possess unique processes for regulation of septum formation. To begin to address this poorly understood aspect of M. tuberculosis physiology, FtsZ inhibitors were used to block cell division and the effects on bacterial morphology and the transcriptional response were examined. Inhibition of septum formation prevented cell division and led to bacterial filamentation. Microarray-based transcriptional profiling allowed the evaluation of multiple metabolic processes in response to inhibition of septum formation and when coupled with bioinformatics provided a means to identify regulatory elements and other gene products that probably influence septum formation. INTRODUCTIONCell division at the molecular level has been well studied in a number of bacteria and it is recognized that septum formation is the first committed step of this event (Harry et al., 1999). In general, inhibition of bacterial division at the point of septum formation is characterized by normal chromosome replication and segregation that is not followed by cellular division leading to a filamentous phenotype . Septum formation is dependent on the assembly of FtsZ into the contractile Z-ring at the site of division (Den Blaauwen et al., 1999;Romberg & Levin, 2003) and additional proteins recruited to the septum site in a sequential fashion, resulting in constriction and cell division. In spite of this biochemical information, the current understanding of regulatory elements and the precise nature of the signals driving the coordination of cell division with other cell cycle processes is largely unknown, especially in Mycobacterium tuberculosis.Many of the proteins involved in cell division, such as FtsZ, are conserved across taxa, while others appear limited to one or a few bacterial groups Margolin, 2000). These include proteins known to interact with FtsZ and that modulate Z-ring assembly Romberg & Levin, 2003). The Z-ring is highly dynamic, and proper assembly of this structure and cell division are strongly influenced by direct interactions of FtsZ with ZipA, ZapA, FtsA, MinD, EzrA and SulA (Harry et al., 1999;Harry, 2001;Migocki et al., 2004;Romberg & Levin, 2003). These factors together with transcriptional regulators form a regulatory network that orchestrates the spatial and temporal control of cell division with other cell cycle processes. However, the underlying molecular mechanisms are only partially understood in model organisms and remain largely unknown for many unrelated organisms.Analysis of the M. tuberculosis genome sequence revealed t...

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Section: Discussionsupporting

confidence: 73%

Section: Effect Of Ftsz Inhibition On Bacterial Viability and Cell Mosupporting

confidence: 76%

Section: Effect Of Ftsz Inhibition On Bacterial Viability and Cell Momentioning

confidence: 99%

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Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis

2006

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“…As a continued study, Ojima et al disclosed that the conjugated ester group when it is coupled with a ring-opened core (TRA 10a (42 in Figure 7) or 10b (43 in Figure 7)) can enhance the potency of taxanederived small molecule targeting at M. tuberculosis FtsZ. Moreover, these compounds are clearly much less cytotoxic than paclitaxel (200-1,000 times less toxic) and 40 against mammalian cells [115].…”

Section: Taxane Derivativesmentioning

confidence: 99%

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

Sun¹,

Wong²

2018

Fighting Antimicrobial Resistance

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“…28,29 The in vitro activities of the ultimate products were evaluated using enzyme inhibition and whole cell antibacterial assays as described previously (Table 1-Table 3). 22,33,34 In general, addition of a bulky substituent at either the ortho, meta or para position of the B ring of 19 or incorporation of most aromatic nitrogen heterocycles resulted in a significant reduction in both enzyme inhibition and antibacterial activity (Table 1 and Table 3). In contrast, introduction of either amino or nitro substituents at the ortho and para positions had only a minimal effect on activity ( Table 2).…”

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confidence: 99%

Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors

Ende

Knudson

Liu

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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In earlier work structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC 90 values of 1-2 µg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and enhance potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide or piperazine functions. Compounds 3c, 3e and 14a show comparable MIC 90 values to that of 19, but have improved ClogP values. KeywordsTuberculosis; Diaryl ether; enoyl reductase; mycolic acids; InhA; isoniazid Tuberculosis (TB) is responsible for more than 1.6 million deaths per annum with 8.8 million new cases being reported each year. These numbers make TB one of the leading infectious causes of death, eclipsed only by AIDS. In addition, according to the World Health Organization, the number of multi-drug-resistant and extensively drug-resistant TB cases is growing with almost a half million new cases being reported each year. Therefore, there is an urgent need to develop novel TB chemotherapeutic agents. 1 *Corresponding authors, PJT: Tel.: (631) 632 7907; Email: peter.tonge@sunysb.edu, RAS: Tel.: (970) 491 1925; Email: richard.slayden@colostate.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In this study we describe two classes of molecules in which alterations have been made to the diphenyl ether 'B' ring. In one series of compounds we have replaced the B ring with isosteric heterocycles that incorporate nitrogen atoms within the ring, thereby causing little steric perturbation to the overall structure of the molecule (Scheme 2). The second series of compounds have nitro, amino, amide and piperazino functionalities incorporated at the ortho, meta, or para positions of the B ring (Scheme 3 and Scheme 4). This second series of compounds was synthesized not only to improve solubility but also to systematically identify positions on the B ring which could be substituted without diminishing biological activity. NIH Public AccessThe synthesis of the heterocyclic diaryl ether compounds was initiated either by nucleophilic aromatic substitution or by Buchwald-Hartwig cross-coupling of the appropriate nitrogen heterocycle with 4-b...

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Targeting FtsZ for Antituberculosis Drug Discovery: Noncytotoxic Taxanes as Novel Antituberculosis Agents

Cited by 102 publications

References 11 publications

Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis

Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors

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