On the nature of<i>Mycobacterium tuberculosis</i>-latent bacilli

Cardona, P-J.

doi:10.1183/09031936.04.00072604

Cited by 100 publications

(84 citation statements)

References 60 publications

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“…The dynamic hypothesis of Cardona (2009) suggests that latent tuberculosis infection is caused by the constant endogenous reinfection of latent bacilli. Considering this hypothesis, constant "escape" of bacilli from granulomas before fibrosis is the primary source of bacteria, reactivation would never occur after a specific time period, unless the host suffered an immunosuppressive episode (Cardona & Ruiz-Manzano, 2004). Of special interest is the finding that foamy macrophages are able to maintain a stressful environment that keeps the bacilli in non-replicating state, but on the other hand, allow them to escape from granulomas, making them more resistant to future stressful conditions (Cardona et al, 2000;2003;Cardona, 2009).…”

Section: Clinical Significance and Role Of Mycobacterial L-formsmentioning

confidence: 99%

Cell Wall Deficiency in Mycobacteria: Latency and Persistence

Маркова¹

2012

Understanding Tuberculosis - Deciphering the Secret Life of the Bacilli

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Section: Clinical Significance and Role Of Mycobacterial L-formsmentioning

confidence: 99%

Cell Wall Deficiency in Mycobacteria: Latency and Persistence

Маркова¹

2012

Understanding Tuberculosis - Deciphering the Secret Life of the Bacilli

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“…This may indicate that, although nonreplicating, dormant cells require some cell wall maintenance and retain limited sensitivity to cell wall inhibitors. For instance, INH monotherapy is known to prevent reactivation in latent TB infection, where M. tuberculosis is thought to persist in a dormant state (31,32).…”

Section: Figmentioning

confidence: 99%

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Lechartier

Cole

2015

Antimicrob Agents Chemother

119

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Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O 2 . CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis. With approximately 9 million incident cases of tuberculosis (TB) worldwide and around 1.5 million deaths in 2012, Mycobacterium tuberculosis infection is one of the most important causes of death from a single infectious agent (1). The spread of multidrug-resistant TB (MDR-TB), namely, with resistance to isoniazid and rifampin, poses additional challenges to treatment with currently available anti-TB drugs. The situation is exacerbated by the increasing emergence of extensively drug-resistant (XDR) strains of M. tuberculosis, which cause diseases essentially untreatable with existing compounds. It is nowadays widely acknowledged that we need to develop new antibiotic combinations for TB and that these new regimens should be tested together at the preclinical stage, rather than testing a series of single drugs separately, in order to fill the TB drug development pipeline more efficiently (2-4).Some of the compounds in advanced clinical trials for TB are molecules that were originally used to treat other infectious diseases and have been repurposed for TB. Among the repurposed molecules, clofazimine (CZM), a riminophenazine originally developed as a drug to treat TB but overlooked for decades, has been used as a standard component of the treatment of leprosy for 50 years. It was recently repurposed for managing MDR-TB cases, notably following the results of the so-called Bangladesh study, which demonstrated that a CZM-containing regimen can cure such resistant cases in 9 to 12 months (5). Grosset et al. demonstrated the substantial benefit of adding CZM to second-line regimens in mice infected with isoniazid-resistant...

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“…This is very unfortunate, because the subject of morphology addresses a fundamental biological question, the significance of which has been decided by the organisms themselves. A simple way to verify this is to take a look at the cultures of M. tuberculosis under different condition inside and outside the host [1]. They become shorter in older cultures, filamentous within macrophages, and ovoid during starvation [2,3].These morphological changes are examples in which cell shape is implicated but not yet proven to be important.…”

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confidence: 99%