In Vitro and In Vivo Activities of New Rifamycin Derivatives Against Mycobacterial Infections

Lounis, Nacer; Roscigno, Giorgio

doi:10.2174/1381612043383287

Cited by 31 publications

(18 citation statements)

References 36 publications

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“…P i -starved bacilli retained susceptibility to the transcriptional inhibitor rifampin (MBC, 0.25 mg/ mL), which has greater activity than isoniazid against nonreplicating latent bacilli [26] and "persisters" [27]. MTB P i -dependent gene expression.…”

Section: P I Limitation In Vitro Restricts Mtb Growthmentioning

confidence: 99%

Phosphate Depletion: A Novel Trigger forMycobacterium tuberculosisPersistence

2009

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Persistent Mycobacterium tuberculosis (MTB) likely encounters a phosphate-limited environment within macrophage phagosomes. We studied MTB growth, antibiotic susceptibility, and gene expression during phosphate limitation. With use of MTB mutants deficient in phosphate-related genes, we assessed bacillary survival under phosphate-limited conditions and in mouse and guinea pig lungs. Phosphate limitation restricted MTB growth in a dose-dependent manner, and phosphate-starved bacilli became phenotypically tolerant to isoniazid. The MTB genes ppk1 and relA were upregulated significantly after phosphate starvation, consistent with inorganic polyphosphate accumulation and MTB stringent response induction. The phosphate-specific transport operon pstS3-pstC2-pstA1 was induced during phosphate starvation and its expression was dependent on the 2-component regulatory system SenX3-RegX3. The MTB gene regX3 appears to be essential for bacillary survival during phosphate limitation and in mammalian lungs. Our data suggest that MTB encounters phosphate-limited conditions during mammalian lung infection and that expression of the phosphate starvation response (PSR) is important for MTB persistence.

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Section: P I Limitation In Vitro Restricts Mtb Growthmentioning

confidence: 99%

Phosphate Depletion: A Novel Trigger forMycobacterium tuberculosisPersistence

2009

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“…[6] However, several side effects have been associated with this drug such as nausea, vomiting, weight loss, hepatotoxicity, skin and A c c e p t e d M a n u s c r i p t gastrointestinal adverse reactions and immune responses. [6][7][8]. As a consequence of the several side effects along with the lengthy treatment period, there is a low adherence to drug administration schedules, which facilitates the development of multi-drug resistant tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer

Bellini

Guimarães

Pacheco

et al. 2015

Journal of Molecular Graphics and Modelling

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The association of the anti-tuberculosis drug rifampicin (RIF) with a 4th-generation poly(amidoamine) (G4-PAMAM) dendrimer was investigated by means of molecular dynamics simulations. The RIF load capacity was estimated to be around 20 RIF per G4-PAMAM at neutral pH. The complex formed by 20 RIF molecules and the dendrimer (RIF20-PAMAM) was subjected to 100 ns molecular dynamics (MD) simulations at two different pH conditions (neutral and acidic). The complex was found to be significantly more stable in the simulation at neutral pH compared to the simulation at low pH in which the RIF molecules were rapidly and almost simultaneously expelled to the solvent bulk. The high stability of the RIF-PAMAM complex under physiological pH and the rapid release of RIF molecules under acidic medium provide an interesting switch for drug targeting since the Mycobacterium resides within acidic domains of the macrophage. Altogether, these results suggest that, at least in terms of stability and pH-dependent release, PAMAM-like dendrimers may be considered suitable drug delivery systems for RIF and derivatives.

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“…1D) and RPT (Fig. 1E) have been investigated by a number of researchers in detail [93]. As determined by MIC, RBT is about 4 to 8 times more active than rifampin (RIF) against MTB and it possesses favorable pharmacokinetic features such as a long half-life and good tissue penetration [94].…”

Section: Rifabutin and Rifapentinementioning

confidence: 99%

Current Status of Some Antituberculosis Drugs and the Development of new Antituberculous Agents with Special Reference to their In Vitro and In Vivo Antimicrobial Activities

Tomioka

2006

CPD

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Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. In particular, the increasing prevalence of multidrug-resistant (MDR)-TB has greatly contributed to the increased difficulties in the control of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new anti-TB drugs without cross-resistance with known antimycobacterial agents is urgently needed. This article deals with the following areas. First, it briefly reviews some recent findings on the pharmacological status of fluoroquinolones and rifamycin derivatives. Second, it describes other types of new agents, such as oxazolidinones (linezolid, PNU-100480), nitroimidazoles (nitroimidazopyran PA-824, metronidazole), 2-pyridone, riminophenazines and diarylquinolines, which are being developed as anti-TB drugs. In addition, the future development of new antitubercular drugs is briefly discussed according to the potential pharmacological targets. New critical information on the whole genome of Mycobacterium tuberculosis (MTB) was recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on MTB genome, drug development using quantitative structure-activity relationship may be possible in the near future.

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In Vitro and In Vivo Activities of New Rifamycin Derivatives Against Mycobacterial Infections

Cited by 31 publications

References 36 publications

Phosphate Depletion: A Novel Trigger forMycobacterium tuberculosisPersistence

Phosphate Depletion: A Novel Trigger forMycobacterium tuberculosisPersistence

Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer

Current Status of Some Antituberculosis Drugs and the Development of new Antituberculous Agents with Special Reference to their In Vitro and In Vivo Antimicrobial Activities

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