Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity against<i>Mycobacterium tuberculosis</i>

Schwartz, Y. Sh.; Душкин, М. И.; Вавилин, В. А.; Мельникова, Е. В.; Khoschenko, O. M.; Va, Kozlov; Agafonov, A. P.; Alekseev, Alexander; Rassadkin, Yu. N.; Shestapalov, A. M.; Azaev, M. Sh.; Saraev, D. V.; Филимонов, П. Н.; Kurunov, Yu. N.; Svistelnik, A. V.; Краснов, В. А.; Pathak, Ashish; Derrick, Steven C.; Reynolds, Robert C.; Morris, Stephen; Блинов, В. М.

doi:10.1128/aac.00362-05

Cited by 12 publications

(10 citation statements)

References 21 publications

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“…Achieving an effective concentration of drug by oral administration and a complete cure is complicated by the difficulty of delivering drugs to the sites deep within the lungs where Mycobacterium tuberculosis resides. Several studies have attempted to improve the delivery of drugs into the lungs [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Such targeted delivery of drugs is expected to improve the treatment of TB, decrease the necessary doses, and reduce systemic sideeffects.…”

Section: Introductionmentioning

confidence: 99%

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

2008

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Abstract. The purpose of this study was to use a four-fluid nozzle spray drier as a new one-step method for preparing rifampicin (RFP)-containing mannitol microparticles. A RFP-acetone/methanol (2:1) solution and aqueous solutions of mannitol (MAN) were simultaneously supplied through different liquid passages of a four-fluid nozzle spray drier and then dried to obtain MAN microparticles containing RFP. Using a cascade impactor, the in vitro aerosol performance of RFP powder and RFP-MAN microparticles with 1:5, 1:10, and 1:20 ratios was compared. The in vivo retention of RFP in the lungs of rats after intratracheal administration of 1:20 RFP-MAN microparticles was also compared. The RFP-MAN microparticles had better aerosol performance than RFP powder and delivery to the lung stages improved as the fraction of MAN was increased. For the 1:20 RFP-MAN microparticles, deposition in stages 2-7 was approximately 43%, which is sufficient for treatment. Approximately 8% of the RFP-MAN microparticles were deposited in stages 6-7, which corresponds to alveoli containing alveolar macrophages. The initial retention of RFP in the lung following pulmonary delivery of 1:20 RFP-MAN microparticles was higher than following oral or intravenous administration of RFP, but the elimination was rapid, resulting in the disappearance of RFP from the lung within 4 h. The plasma concentrationtime profile of RFP after intratracheal administration of 1:20 RFP-MAN microparticles was consistent with the profile for RFP retention in the lung. Addition of cholesterol or phosphatidylcholine to RFP had little effect on its retention in the lung. The RFP-MAN microparticles were effective for delivery of RFP to the lung, but the RFP rapidly removed from the lung into the blood circulation. This study demonstrated that RFP-containing MAN microparticles prepared in one step using the four-fluid nozzle spray drier efficiently deliver RFP to the lung, although methods must be developed to prolong its retention and improve targeting to alveolar macrophages.

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Section: Introductionmentioning

confidence: 99%

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

2008

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“…tuberculosis within macrophages [36]. But this conjugation is not supportive for conjugation with PA-824 since Carboxymethylglucan has been shown to have antioxidant activities [37] which could counteract the essential ROS generation by PA-824 for bactericidal activity.…”

Section: Discussionmentioning

confidence: 99%

Bactericidal activity of PA-824 against Mycobacterium tuberculosis under anaerobic conditions and computational analysis of its novel analogues against mutant Ddn receptor

Somasundaram¹,

Anand

Venkatesan

et al. 2013

BMC Microbiol

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BackgroundThe resurgence of multi-drug resistant tuberculosis (MDR-TB) and HIV associated tuberculosis (TB) are of serious global concern. To contain this situation, new anti-tuberculosis drugs and reduced treatment regimens are imperative. Recently, a nitroimidazole, PA-824, has been shown to be active against both replicating and non-replicating bacteria. It is activated by the enzyme Deazaflavin-dependent nitroreductase (Ddn) present in Mycobacterium tuberculosis which catalyzes the reduction of PA-824, resulting in the release of lethal reactive nitrogen species (RNS) within the bacteria. In this context, PA-824 was analyzed for its activity against latent tuberculosis under anaerobic conditions and compared with rifampicin (RIF) and pyrazinamide (PZA). Recent mutagenesis studies have identified A76E mutation which affects the above mentioned catalysis and leads to PA-824 resistance. Hence, novel analogues which could cope up with their binding to mutant Ddn receptor were also identified through this study.ResultsPA-824 at an optimum concentration of 12.5 μg/ml showed enhanced bactericidal activity, resulting in 0 CFU/ml growth when compared to RIF and PZA at normal pH and anaerobic condition. Further docking studies revealed that a combinatorial structure of PA-824 conjugated with moxifloxacin (ligand 8) has the highest binding affinity with the wild type and mutant Ddn receptor.ConclusionsPA-824 has been demonstrated to have better activity under anaerobic condition at 12.5 μg/ml, indicating an optimized dose that is required for overcoming the detoxifying mechanisms of M. tuberculosis and inducing its death. Further, the development of resistance through A76E mutation could be overcome through the in silico evolved ligand 8.

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“…Thus, Schwartz and coworkers explored the use of moxifloxacin-conjugated dansylated carboxymethylglucan (45). It was found that the conjugated glucan was concentrated in the macrophages of lungs and spleen.…”

Section: Treatment Of Tb and Other Mycobacterial Diseasementioning

confidence: 98%

Update in Tuberculosis 2006

Yew

Leung²

2007

Am J Respir Crit Care Med

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Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity againstMycobacterium tuberculosis

Cited by 12 publications

References 21 publications

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

Bactericidal activity of PA-824 against Mycobacterium tuberculosis under anaerobic conditions and computational analysis of its novel analogues against mutant Ddn receptor

Update in Tuberculosis 2006

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