Therapeutic potential of FtsZ inhibition: a patent perspective

Awasthi, Divya; Kumar, Kunal; Ojima, Iwao

doi:10.1517/13543776.2011.568483

Cited by 47 publications

(25 citation statements)

References 108 publications

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“…[4][5][6][7] ftsZ is the most conserved of all known bacterial cell-division genes and encodes the bacterial proto-ring protein FtsZ, and so plays a key role in bacterial cell division. It is the first protein to localize at the site of incipient division and functions as a GTP-dependent guanosine triphosphatase, like the tubulin protein in eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene

Liang

Hé

Xia

et al. 2015

International Journal of Infectious Diseases

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Section: Introductionmentioning

confidence: 99%

Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene

Liang

Hé

Xia

et al. 2015

International Journal of Infectious Diseases

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“…The bacterial protein FtsZ has been identified as an appealing new target for the development of antibiotics that can be used to treat infections caused by multidrug-resistant (MDR) bacterial pathogens (10)(11)(12)(13)(14). The appeal of FtsZ as an antibiotic target lies in the essential role that the protein plays in bacterial cell division (cytokinesis).…”

mentioning

confidence: 99%

TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

Kaul

Mark

Zhang³

et al. 2015

Antimicrob Agents Chemother

109

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The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo, TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF 3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-ofcare drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development. Bacterial resistance has emerged as a global problem. The Centers for Disease Control and Prevention (CDC) have identified methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) as being two major antibiotic resistance threats (1). Typically, MRSA strains are resistant not only to the penicillins but also to other classes of antibiotics, including the tetracyclines, the macrolides, the aminoglycosides, and clindamycin (2-4). Current standard-of-care (SOC) drugs for the treatment of MRSA infections are therefore limited to a few drugs, which include vancomycin, daptomycin, and linezolid (3). However, resistance to these SOC drugs is already on the rise, and the clinical utility of these drugs is likely to diminish in the future (3, 5-9).The bacterial protein FtsZ has been identified as an appealing new target for the development of antibiotics that can be used to treat infections caused by multidrug-resistant (MDR) bacterial pathogens (10-14). The appeal of FtsZ as an antibiotic target lies in the essential role that the protein plays in bacterial cell division (cytokinesis). Furthermore, FtsZ is prokaryote specific with no known eukaryotic homolog. FtsZ self-polymerizes in a GTP-dependent manner to form a ring-like structure (the Z-ring) at midcell that serves as a scaffold for the recruitment and organization of other critical components for proteoglycan synthesis, septum formation, and cell division (15)(16)(17)(18)(19)(20).The substituted benzamide derivative PC190723 has been shown to inhibit bacterial cell div...

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“…The process of bacterial cell division is a novel and attractive target for new antibacterial drug discovery (8)(9)(10)(11)(12)(13). FtsZ is considered to be the major protein of the bacterial cell division machinery (divisome) (14,15).…”

mentioning

confidence: 99%

An Improved Small-Molecule Inhibitor of FtsZ with Superior In Vitro Potency, Drug-Like Properties, and In Vivo Efficacy

Stokes¹,

Baker²,

Bennett³

et al. 2013

Antimicrob Agents Chemother

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The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 g/ml against all staphylococcal species, including methicillin-and multidrug-resistant Staphylococcus aureus and Staphylococcus epidermidis. Compound 1 inhibited an S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in a murine model of systemic S. aureus infection and caused a significant decrease in the bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was designated compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.

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Therapeutic potential of FtsZ inhibition: a patent perspective

Cited by 47 publications

References 108 publications

Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene

Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene

TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

An Improved Small-Molecule Inhibitor of FtsZ with Superior In Vitro Potency, Drug-Like Properties, and In Vivo Efficacy

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