Dormancy models for &lt;italic&gt;Mycobacterium tuberculosis&lt;/italic&gt;: A minireview

Alnimr, Amani

doi:10.1590/s1517-838246320140507

Cited by 26 publications

(27 citation statements)

References 39 publications

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“…Lethal action of the fluoroquinolones, including moxifloxacin, is suggested to occur through 2 steps, formation of bacteriostatic quinolone‐gyrase‐DNA complexes followed by chromosome fragmentation . A central feature of TB is the tendency of MTB to enter a dormant state in which the bacterium is likely to exhibit low susceptibility to chemotherapeutic agents . Moxifloxacin has been shown to have a unique ability to kill mycobacteria in the absence of ongoing protein synthesis or while in a dormant state, which is important for the eradication of the TB infection and prevention of relapse …”

Section: Resultsmentioning

confidence: 99%

“…49,50 A central feature of TB is the tendency of MTB to enter a dormant state in which the bacterium is likely to exhibit low susceptibility to chemotherapeutic agents. 51 Moxifloxacin has been shown to have a unique ability to kill mycobacteria in the absence of ongoing protein synthesis or while in a dormant state, which is important for the eradication of the TB infection and prevention of relapse. 49,50 Pharmacokinetics Absorption.…”

Section: Mechanism Of Action and Activity Of Moxifloxacin Againstmentioning

confidence: 99%

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A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

Naidoo

McIlleron

et al. 2017

The Journal of Clinical Pharma

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Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis (MDR TB) and is being investigated in novel drug regimens with pretomanid, bedaquiline and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid mono-resistance. Evidence suggests that the standard 400mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive inter-individual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is however needed, to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review, the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens.

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Section: Resultsmentioning

confidence: 99%

Section: Mechanism Of Action and Activity Of Moxifloxacin Againstmentioning

confidence: 99%

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

Naidoo

McIlleron

et al. 2017

The Journal of Clinical Pharma

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“…(175, 184–187)], most without reactivation, while probably 50–100% are infected with H. pylori , most without getting ulcers or worse (188, 189). As with the risk factors in Table 1, the organisms are merely or equivalently “risk factors” for these infectious diseases and are effectively seen as causative only when the disease is actually manifest.…”

Section: Prevalence Of Dormant Persistent or Latent Bacteria In Infmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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“…Hypoxia induces many changes in mycobacteria. Both in microaerophilic and anaerobic cultures, Mtb is known to develop a thickened cell wall which may be important for adaptation to low oxygen conditions (52). However, the selected set of genes is shown to be extremely down-regulated under hypoxia, agreeing with previously published data (52), and suggesting that maybe the cell wall thickening does not occur in the outer layer.…”

Section: Resultsmentioning

confidence: 99%

“…Both in microaerophilic and anaerobic cultures, Mtb is known to develop a thickened cell wall which may be important for adaptation to low oxygen conditions (52). However, the selected set of genes is shown to be extremely down-regulated under hypoxia, agreeing with previously published data (52), and suggesting that maybe the cell wall thickening does not occur in the outer layer. On the contrary, some regulatory genes, members of the DosT regulon, namely devR, devS and dosT were shown to be highly up-regulated at hypoxic conditions (Figure 6), which is also supported by previous studies (52-54).…”

Section: Resultsmentioning

confidence: 99%

Revisiting the expression signature of pks15/1 unveils regulatory patterns controlling phenolphtiocerol and phenolglycolipid production in pathogenic mycobacteria

Ramos

Gordon

Cunha

2020

Preprint

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AbstractOne of the most relevant and exclusive characteristics of mycobacteria is its cell wall, composed by mycolic acids. Amid these are two related families of glycosylated lipids, diphthioceranates and phthiocerol dimycocerosate (PDIM) and its variant phenolic glycolipids (PGL). PGL have been associated with cell wall impermeability, phagocytosis, defence against nitrosative and oxidative stress and, supposedly, biofilm formation. In bacteria from the Mycobacterium tuberculosis complex, the biosynthetic pathway of the phenolphthiocerol moiety of PGL depends upon the expression of several genes encoding type I polyketide synthases (PKS), namely ppsA-E and pks15/1 constituting the PDIM + PGL locus, highly conserved in PDIM/PGL-producing strains. Consensus has not been achieved regarding the genetic organization of pks15/1 locus and little effort has been put on the disclosure of its transcriptional signature. Here we explore publicly available datasets of transcriptome data (RNA-seq) from more than 100 experiments in 40 growth conditions to outline the transcriptional structure and signature of pks15/1 and use a differential expression approach to infer the regulatory patterns involving these and related genes. We show that pks1 is highly correlated with fadD22, Rv2949c, lppX, fadD29 and, also, pks6 and pks12, with the first three putatively integrating a polycistronic structure. We evidence dynamic heterogeneity of transcription within the genes involved in phenolphtiocerol and phenolglycolipid production, most exhibiting up-regulation upon acidic pH and antibiotic exposure and down-regulation under hypoxia, dormancy, and low/high iron concentration. We finally propose a model based on transcriptome data in which σD positively regulates pks1, pks15 and fadD22, while σB and σE factors exert negative regulation at an upper level.

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Dormancy models for <italic>Mycobacterium tuberculosis</italic>: A minireview

Cited by 26 publications

References 39 publications

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

A Dormant Microbial Component in the Development of Preeclampsia

Revisiting the expression signature of pks15/1 unveils regulatory patterns controlling phenolphtiocerol and phenolglycolipid production in pathogenic mycobacteria

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