A Novel Mechanism of Growth Phase-dependent Tolerance to Isoniazid in Mycobacteria

Niki, Makoto; Tateishi, Yoshitaka; Ozeki, Yuriko; Kirikae, Teruo; Lewin, Astrid; Inoue, Yusuke; Matsumoto, Makoto; Dahl, John L.; Ogura, Hisashi; Kobayashi, Keiko; Matsumoto, Sohkichi

doi:10.1074/jbc.m111.333385

Cited by 48 publications

(55 citation statements)

References 52 publications

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“…Although the enoyl-acyl carrier protein reductase InhA is the most described, other mechanisms and enzymes may be involved, such as the human arylamine N-acetyltransferase (NAT) polymorphism, the TB NAT that is also required for mycolic acid synthesis, the MDP1 gene, or even the loss of a sigma factor (34)(35)(36)(37)(38). Mycobacterial NudC may also play an important role in the inactivation of INH (39).…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

et al. 2013

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e As a follow-up of the "spoligoriftyping" development, we present here an extension of this technique which includes the detection of isoniazid resistance-associated mutations in a new 59-plex assay, i.e., tuberculosis-spoligo-rifampin-isoniazid typing (TB-SPRINT), running on microbead-based multiplexed systems. This assay improves the synergy between clinical microbiology and epidemiology by providing (i) mutation-based prediction of drug resistance profiles for patient treatment and (ii) genotyping data for tuberculosis (TB) surveillance. This third-generation microbead-based high-throughput assay for TB runs on the Luminex 200 system and on the recently launched MagPix system (Luminex, Austin, TX). Spoligotyping patterns obtained by the TB-SPRINT method were 100% (n ‫؍‬ 85 isolates; 3,655/3,655 spoligotype data points) concordant with those obtained by microbead-based and membrane-based spoligotyping. Genetic drug susceptibility typing provided by the TB-SPRINT method was 100% concordant with resistance locus sequencing (n ‫؍‬ 162 for rpoB gene sequencing and n ‫؍‬ 76 for katG and inhA sequencing). Considering phenotypic drug susceptibility testing (DST) as the reference method, the sensitivity and specificity of TB-SPRINT regarding Mycobacterium tuberculosis complex (n ‫؍‬ 162 isolates) rifampin resistance were both 100%, and those for isoniazid resistance were 90.4% (95% confidence interval, 85 to 95%) and 100%, respectively. Used routinely in national TB reference and specialized laboratories, the TB-SPRINT assay should simultaneously improve personalized medicine and epidemiological surveillance of multidrug-resistant (MDR) TB. This assay is expected to play an emerging role in public health in countries with heavy burdens of MDR TB and/or HIV/TB coinfection. Application of this assay directly to biological samples, as well as development for extensively drug-resistant (XDR) TB detection by inclusion of second-line antituberculosis drug-associated mutations, is under development. With bioinformatical methods and data mining to reduce the number of targets to the most informative ones, locally adapted formats of this technique can easily be developed everywhere.

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Section: Discussionmentioning

confidence: 99%

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

et al. 2013

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“…Although M. tuberculosis can inhibit maturation of the phagosome and limit its acidification to a pH of ϳ6.2 by excluding vacuolar proton-ATPase in immunologically naive macrophages, this block is relieved and the phagosomal compartment acidifies to a pH of 4.5 to 5.0 in gamma interferon (IFN-␥)-activated macrophages (56). Importantly, exposure of M. tuberculosis to a pH of Ͻ5.5 in vitro leads to growth arrest (57,58) and phenotypic tolerance to isoniazid (59). The in vivo relevance of the acidic pH model of M. tuberculosis dormancy is underscored by the fact that pyrazinamide, which exhibits antituberculous activity only under acidic conditions (60), is highly active in combination with rifampin for the treatment of LTBI (3).…”

Section: Stresses Simulating the Environment Within The Macrophage Phmentioning

confidence: 99%

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

Dutta

Karakousis

2014

Microbiol Mol Biol Rev

201

174

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SUMMARY The aim of this review is to present the current state of knowledge on human latent tuberculosis infection (LTBI) based on clinical studies and observations, as well as experimental in vitro and animal models. Several key terms are defined, including “latency,” “persistence,” “dormancy,” and “antibiotic tolerance.” Dogmas prevalent in the field are critically examined based on available clinical and experimental data, including the long-held beliefs that infection is either latent or active, that LTBI represents a small population of nonreplicating, “dormant” bacilli, and that caseous granulomas are the haven for LTBI. The role of host factors, such as CD4 + and CD8 + T cells, T regulatory cells, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ), in controlling TB infection is discussed. We also highlight microbial regulatory and metabolic pathways implicated in bacillary growth restriction and antibiotic tolerance under various physiologically relevant conditions. Finally, we pose several clinically important questions, which remain unanswered and will serve to stimulate future research on LTBI.

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“…There are several mutations in different genes, but particularly in codon 315 of the katG gene, the inhA regulatory region and the ahpC-oxyR intergenic region which are associated with isoniazid resistance (Hazbon et al, 2006;Mokrousov et al, 2002;Blanchard, 1996;Gillespie, 2002). In the case of INH-resistant strains, the most common cause of resistance is a mutation in or the downregulation of the katG gene which reduces the rate at which the pro-drug converts into its active state (Rouse et al, 1995;Niki et al, 2012). One can describe the formation of the active drug as:…”

Section: Resultsmentioning

confidence: 99%

“…In the later stages of the disease, the model proposed here may not apply because INH has significantly lower effectiveness against non-replicating bacilli (Niki et al, 2012). Initially all bacilli have the same cell wall thickness.…”

Section: Mathematical Modelmentioning

confidence: 99%