Sandeep Tyagi's research while affiliated with Johns Hopkins University and other places
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Publications (90)
Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG, encoding the pro-drug activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA...
The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We...
Centrally necrotizing granulomas that harbor Mycobacterium tuberculosis (Mtb) are the hallmark of human tuberculosis (TB). New anti-TB therapies will need to effectively penetrate the cellular and necrotic, non-vascularized compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ‑043 is a novel antibiotic showing good...
The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome...
As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC50] = 0.07 μM), is active against extracellular bacteria in cholesterol-c...
As a result of a high-throughput compound screening campaign of Mycobacterium tuberculosis infected macrophages, a new preclinical drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (IC 50 = 0.07 µM), is active against extracellular bacteria in cholesterol-containing culture med...
Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans . Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered...
TB drug, regimen and vaccine development rely heavily on preclinical animal experiments, and quantification of bacterial and immune response dynamics are essential for understanding drug and vaccine efficacy. A mechanism-based model was built to describe Mycobacterium tuberculosis H37Rv infection in BALB/c and athymic nude mice over time, which con...
Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans . Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered...
Background:
Linezolid (LZD) is bactericidal against Mycobacterium tuberculosis, but has treatment-limiting toxicities. Better understanding of exposure-response relationships governing LZD efficacy and toxicity will inform dosing strategies. Because in vitro monotherapy studies yielded conflicting results, we explored LZD pharmacokinetic/pharmacod...
Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed tha...
The potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following...
The potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following...
Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) may be an effective alternative. With the achievemen...
Mycolactone values.
(PDF)
Footpad swelling grades.
(PDF)
Dose- and time- dependence of skin discoloration in mice treated with clofazimine (CFZ).
1) mice treated with rifampicin (RIF) and 25 mg/kg CFZ for 6 weeks; 2) mice treated with RIF and 12.5 mg/kg CFZ for 6 weeks; 3) mice treated with RIF and 25 mg/kg for 4 weeks and assessed two weeks later; and, 4) mice treated with rifampicin and streptomycin (S...
Scheme of the experiment.
(PDF)
The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment-shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin disco...
Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search f...
CD4 and CD8 T cell responses induced by MVATG18598 monitored by an intracellular IFNγ, TNFα and IL2 staining assay in naive BALB/c mice.
Mice were immunized once with MVATG18598 or the empty vector MVATGN33.1, as a negative control. Cells were stimulated with Mtb peptide pools, the MVA vector-specific VGP peptide or an irrelevant E7 peptide. Result...
Peptide library and triple ICS assay.
(DOCX)
Summary of immune responses induced by MVATG18598 vaccine in naive BALB/c, C57BL/6 and CB6F1 mice.
Resuscit., Resuscitation. IFNγ ELISpot: group median value of spots detected using the following ranking: -, median < cut-off; +, 1x cut-off < median < 2x cut-off; ++, 2x cut-off < median < 3x cut-off; +++, 3x < median < 5x; ++++, median > 5x cut-off....
New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) + pretomanid (PMD) + pyrazinamide (PZA) and of PMD + moxifloxacin (MXF) + PZA shorten the treatment duration necessary to prevent relap...
The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis
and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant
tuberculosis. In a limited number of bedaquiline-treated patients reported to date, up...
New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid
(PMD) is a nitroimidazole in phase 3 trials with significant bactericidal activity alone and in combination with bedaquiline
(BDQ) and/or pyrazinamide (PZA). We previously showed the novel combination of BDQ+PMD plus the oxazo...
The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized...
Survival of mice by treatment group.
(A). Distribution of swelling grades at the initiation of treatment. Swelling was similar at baseline in the RIF+CLR and RIF+CFZ groups as well as the CFZ only group but markedly less in the RIF+STR positive control group. (B) Antibiotic treatment prevented euthanasia in mice with footpad lesions resulting from...
Skin discoloration in mice receiving CFZ.
Skin color is normal in mouse treated with RIF+CLR for 6 weeks (left) whereas in mice treated with RIF+CFZ for 4 weeks (right) the ears have a yellow-orange tinge and tail and footpads are dark red. The discoloration was no longer apparent 3 weeks after the cessation of drug treatment.
(TIF)
CFU, Mycolactone A/B, Footpad swelling records, and CFZ levels.
(XML)
Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, su...
Mycobacterium avium complex is the most common cause of non-tuberculous mycobacterial lung disease worldwide; yet, an optimal treatment regimen for M. avium complex infection has not been established. Clarithromycin is accepted as the cornerstone drug for treatment of M. avium lung disease; however, good model systems, especially animal models, are...
Significance
The infectious disease tuberculosis (TB) is a major public health problem that affects millions of people worldwide. TB treatment consists of a multidrug regimen that needs to be taken for a minimum of 6 mo, and lack of adherence to this regimen is associated with treatment failure and emergence of drug resistance. In a mouse model of...
Bedaquiline is a newly approved drug for the treatment of multidrug-resistant tuberculosis, but there are concerns about its
safety in humans. We found that the coadministration of verapamil with subinhibitory doses of bedaquiline gave the same bactericidal
effect in mice as did the full human bioequivalent bedaquiline dosing. Adding verapamil to b...
The mechanism of action of pyrazinamide, a key sterilizing drug in the treatment of tuberculosis, remains elusive; pyrazinamide is a pro-drug that requires activation by a bacterial-encoded enzyme, and its activity is most apparent on non-replicating Mycobacterium tuberculosis. Recently, it has been suggested that pyrazinamide might exert also some...
Diagnosis of the neglected tropical disease, Buruli ulcer, can be made by acid-fast smear microscopy, specimen culture on mycobacterial growth media, polymerase chain reaction (PCR), and/or histopathology. All have drawbacks, including non-specificity and requirements for prolonged culture at 32°C, relatively sophisticated laboratory facilities, an...
Rationale:
Although observational studies suggest that clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for the treatment of this disease has never been systematically evaluated.
Objectives:
Our goal was to directly compare the activity of a standard second-line drug regimen w...
Rationale:
A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy.
Objectives:
Using mice, a mammalian model known to p...
Rationale:
High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown....
Background
Since 2004, treatment of Mycobacterium ulcerans disease, or Buruli ulcer, has shifted from surgery to daily treatment with streptomycin (STR) + rifampin (RIF) for 8 weeks. For shortening treatment duration, we tested the potential of daily rifapentine (RPT), a long-acting rifamycin derivative, as a substitute for RIF.
Methodology/Princi...
Background:
Mycobacterium xenopi is a common agent of non-tuberculous mycobacterial lung diseases in Europe. However, an optimal treatment regimen for M. xenopi infection has not yet been established. Appropriate in vitro and in vivo model systems are needed for characterization of the activity of potential drugs and drug combinations against M. x...
Background & objectives:
Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such an...
Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid)
and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between
isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because ison...
PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better unde...
It is widely believed that persistent Mycobacterium tuberculosis inhabits necrotic lung granulomas in humans and that the microenvironmental conditions encountered therein render the bacilli phenotypically tolerant to antibiotics, accounting for the long duration required for successful treatment of tuberculosis (TB). To validate this belief, we di...
It has been hypothesized that the virulence of lab-passaged Mycobacterium tuberculosis and recombinant M. tuberculosis mutants might be reduced due to multiple in vitro passages, and that virulence might be augmented by passage of these strains through mice before quantitative virulence testing in the mouse or guinea pig aerosol models.
By testing...
Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 17...
We recently reported strong bactericidal activity of the oxazolidinone PNU-100480 and its ability to increase the initial bactericidal effect of various combinations of first-line tuberculosis drugs and moxifloxacin in a murine model.
To investigate whether the addition of PNU-100480 to the standard first-line regimen of rifampin, isoniazid, and py...
New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of
1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosp...
To investigate the antagonism between isoniazid (INH) and rifampin (rifampicin) (RIF)-pyrazinamide (PZA) combination observed
in Mycobacterium tuberculosis-infected mice, extensive pharmacokinetic studies of INH were performed and followed by experiments to assess the impact of
increasing doses of INH on the antimicrobial activity of RIF-PZA combin...
Oxazolidinone antibiotics have activity against Mycobacterium tuberculosis. Linezolid, the only marketed oxazolidinone, has been used off-label in combination regimens to treat multidrug-resistant tuberculosis, but its precise contribution to the efficacy of such combinations is unclear. Another oxazolidinone, PNU-100480, has been demonstrated to h...
Tuberculosis of the central nervous system (CNS) is a serious, often fatal disease primarily affecting young children. It develops after hematogenous dissemination and subsequent invasion of the CNS by Mycobacterium tuberculosis. The microbial determinants involved in CNS disease are poorly characterized.
Hematogenously disseminated M. tuberculosis...
Background: In mice infected with Mycobacterium tuberculosis (M.tb), RZ is more active than RZ+H, suggesting that H antagonizes the activity of RZ. Whether such antagonism occurs in humans is unknown. In mice, H is often dosed at 25mg/kg/d, i.e., 5 times the human dose of 5mg/kg/d, producing a Cmax that is 4 times the human Cmax but an AUC that is...
Background: Linezolid (LZD), has an MIC90 of 1 mg/L vs. Mycobacterium tuberculosis (Mtb) and is being used to treat multidrug-resistant (MDR) TB. PNU-100480 (PNU) has similar in vitro activity but was more active in a short-term mouse model. We studied the dose-ranging activity of LZD and PNU and their activity in combination with existing TB drugs...
PA-824 is a nitroimidazo-oxazine in clinical testing for the treatment of tuberculosis. We report that the novel combination
of PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than the first-line regimen of rifampin, isoniazid, and
pyrazinamide. If applicable to humans, regimens containing this combination may radically shorten the t...
PA-824 is in phase II clinical testing to treat tuberculosis. At a dose of 100 mg/kg of body weight, it has demonstrated bactericidal activity during the initial and continuation phases of treatment in a murine model of tuberculosis. In a prior study, substitution of PA-824 for isoniazid in the first-line regimen of rifampin, isoniazid, and pyrazin...
Background:
Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rif...
Alternate sigma factors have been implicated in the survival of mycobacteria in response to specific stresses. To characterize
the role of SigM in Mycobacterium tuberculosis, a sigM deletion mutant was generated by allelic exchange in the virulent CDC1551 strain. Comparing the wild-type and ΔsigM strains by complete genomic microarray, we observed...
Combination therapy is the most effective strategy to prevent emergence of resistance during tuberculosis (TB) treatment. Another strategy, albeit theoretical, is to limit the time that drug concentrations fall in the "mutant selection window" (MSW) between the MIC and the mutant prevention concentration (MPC). Drug concentrations above the MPC pre...
The in vivo rate of proliferation of Mycobacterium tuberculosis the causative agent of tuberculosis, has been linked to the rate of progression and severity of disease. Here, we report
that deletion of the gene MT2175 (Rv2115c), a putative mycobacterial proteasome–associated AAA-ATPase, leads to a reduction
in the growth rate of M. tuberculosis in...
Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substitut...
Priorities for developing improved regimens for treatment of latent tuberculosis (TB) infection include (1) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2) developing and evaluating regimens that are active against multidrug-resistant organisms.
By using a previously validated murine model th...
Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted t...
The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line reg...
The nitroimidazopyran PA-824 has potent in vitro activity against Mycobacterium tuberculosis, a narrow spectrum of activity limited primarily to the M. tuberculosis complex, and no demonstrable cross-resistance to a variety of antituberculosis drugs. In a series of experiments, we sequentially
characterized the activity of PA-824 in an experimental...
The mechanisms by which Mycobacterium tuberculosis elicits disease are complex, involving a large repertoire of bacterial genes that are required for in vivo growth and survival.
To identify such genes, we utilized a high-throughput microarray detection method to rapidly screen hundreds of unique, genotypically
defined transposon mutants for in viv...
During infection Mycobacterium tuberculosis is exposed to several environmental conditions depending on the stage and severity of the disease. To survive, M. tuberculosis uses alternate sigma factors to regulate its gene expression in response to the changing host environment. In order to better understand the way in which stress response genes are...
In a recent experimental study using the mouse model of tuberculosis, treatment with a combination of rifampin, moxifloxacin, and pyrazinamide was able to shorten the time to negative lung cultures by up to 2 months compared with the standard regimen of rifampin, isoniazid, and pyrazinamide. To confirm that this substitution of moxifloxacin for iso...
Bacterial alternative RNA polymerase sigma factors are key global adaptive response regulators with a likely role in Mycobacterium tuberculosis pathogenesis. We constructed a mutant lacking the sigma factor gene, sigC, by allelic exchange, in the virulent CDC1551 strain of M. tuberculosis and compared the resulting mutant with the isogenic wild-typ...
The Mycobacterium tuberculosis alternate sigma factor, SigF, is expressed during stationary growth phase and under stress conditions in vitro. To better understand the function of SigF we studied the phenotype of the M. tuberculosis DeltasigF mutant in vivo during mouse infection, tested the mutant as a vaccine in rabbits, and evaluated the mutant'...
The rabbit model of tuberculosis (TB) is important because rabbits develop a disease that is similar to TB in humans, namely, granulomas with caseous necrosis, liquefaction, and cavities. We describe here a comparison of inbred and outbred New Zealand White rabbits infected by aerosol with either Mycobacterium tuberculosis Erdman or H37Rv strain. F...
Tuberculosis continues to be a major cause of morbidity and mortality in the world. The expansion of tuberculosis control programs has been limited by the lengthy and cumbersome nature of current chemotherapeutic regimens. A new drug that improves the sterilizing activity of current regimens would reduce the duration of therapy without sacrificing...
To develop a murine model of paucibacillary tuberculosis for experimental chemotherapy of latent tuberculosis infection, mice
were immunized with viable Mycobacterium bovis BCG by the aerosol or intravenous route and then challenged six weeks later with virulent Mycobacterium tuberculosis. The day after immunization, the counts were 3.71 ± 0.10 log...
The rabbit model of tuberculosis has been used historically to differentiate between Mycobacterium tuberculosis and Mycobacterium bovis based on their relative virulence in this animal host. M. tuberculosis infection in market rabbits is cleared over time, whereas infection with M. bovis results in chronic, progressive, cavitary disease leading to...
The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infect...
Moxifloxacin (MXF) is a new 8-methoxyquinolone with potent activity against Mycobacterium tuberculosis and a half-life of 9 to 12 h in humans. Previous in vivo studies using daily doses of 100 mg/kg of body weight have demonstrated bactericidal activity comparable to that of isoniazid (INH) in a murine model of tuberculosis (TB). Recent pharmacokin...
Citations
... In mouse models, BTZ-043 has been found to be more effective than INH [92,93]. Treu et al. [94] used high-resolution MALDI imaging to investigate the spatial and temporal distribution of BTZ-043 in centrally necrotizing granulomas harboring MTB. The researchers found an early accumulation of BTZ-043 in the lipid-rich foamy macrophage zone, suggesting that these immune cells act as a drug reservoir. ...
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... Indeed, once such liabilities are known, one can try to engineer around them using medicinal chemistry to achieve more potent compounds. 21,22 For example, spectinomycin is a potent translation inhibitor but has poor antitubercular activity due to drug efflux. Structure-based design was used to generate spectinomycin analogs that are much more potent because they avoid drug efflux. ...
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... Mtb-infected macrophages. 316 Intriguingly, several indepth analyses of the Mtb survival cycle have revealed that cholesterol metabolism plays a pivotal role in facilitating Mtb's survival within macrophages. 317 In fact, in the absence of cholesterol utilization, Mtb is unable to establish an effective infection in macrophages and cannot effectively elicit pathogenesis. ...
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... The compound GSK 2556286 (GSK-286), interfering with mycobacterial cholesterol catabolism, is currently in the first phase of clinical trials, while compounds TBA-7371 inhibits the decaprenylphosphoryl-β-D-ribose-2 ′ -epimerase (DprE1), a critical enzyme in the synthesis of the mycobacterial cell wall. SPR720, which inhibits the bacterial DNA gyrase (GyrB), is also undergoing Phase II clinical trials [30][31][32][33]. ...
... Notably, the relapse rate was 25% in the group treated with rifampin and clarithromycin. Moreover, the authors evaluated the dose-ranging action of telacebec alone and in combination with rifampicin and discovered that rifampicin had no effect on telacebec activity [60]. A different promising molecule is TB47, which, in combination with oral antibiotics (rifampicin, clarithromycin, and clofazimine), can lead to the cure of BU in less than 2 weeks, provided that the treatment is administered daily and in 3 weeks if it is administered twice a week [61]. ...
... This mechanism is responsible for the exposuredependent hematological and neuropathic toxicity of LZD. Although oxazolidinone toxicity attributable to inhibition of mitochondrial protein synthesis can be measured in mice (19), the model has not been sufficiently validated for this purpose. ...
... PK data were described using one-or two-compartment models with first order absorption with or without delay, and saturable elimination when necessary. Bacterial growth dynamics without treatment were described using our previously published baseline model (supplementary equation S1) [8]. The baseline model captures the decreased rate of growth over time and attributes the decline to time-and bacteria-dependent immune control over the infection. ...
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... Nevertheless, they may be relevant as third-line agents (when used in combination) or in other future applications of the trial. Novel antimicrobials with reported M. ulcerans activity include pretomanid [37], bedaquiline [50] and telacebec [51]; we hope to test this isolate against these promising antimicrobials with a view to future clinical trials, as resources allow. ...
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... To directly demonstrate whether the resilient microbiome was functionally resistant to antibiotic disruption, we colonized mice by fecal matter transplant (FMT) with pooled stool from three individuals who completed MDR TB treatment (TC) or pooled from three healthy community controls (HC) (21). After FMT, mice were treated with 1 week of bedaquiline or vehicle as in (76,77) (Fig. 6A). We first examined the mouse microbiome immediately after ampicillin, vancomycin, neomycin, and metronidazole (AVNM) treatment and found no difference between mice scheduled to receive TC versus HC FMT, apart from each being enriched in a different Streptococcus phylotype ( fig. ...
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... Dans la même idée, l'utilisation de forte dose de rifapentine, une rifamycine à demi-vie longue, devrait permettre un traitement intermittent comme démontré par Chauffour et al. où l'utilisation de rifapentine associée à la clarithromycine 2 ou 3 jours par semaine a permis d'obtenir une stérilisation des cultures après 8 semaines de traitement [92]. L'utilisation de clofazimine, un antibiotique utilisé dans la lèpre et dans la tuberculose, s'est avérée prometteuse pour raccourcir le traitement de l'UB en association avec la rifampicine ou avec la rifapentine [93,94]. Finalement, c'est l'apparition d'un nouvel antibiotique non encore commercialisé, le télacébec qui est une imidazopyridine qui donne les résultats les plus encourageants pour simplifier le traitement de l'UB. ...
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