In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis

Martins, Marta; Schelz, Zsuzsanna; Martins, Ana M.; Molnár, Joséph; Hajós, György; Riedl, Zsuzsanna; Viveiros, Miguel; Yalçın, İsmail; Aki-Sener, Esin; Amaral, Leonard

doi:10.1016/j.ijantimicag.2006.10.013

Cited by 63 publications

(41 citation statements)

References 7 publications

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“…There has been increasing interest in the possible use of phenothiazines for the treatment of tuberculosis (2,23,30). This is due in part to the increase in multidrug-resistant and extensively drug-resistant tuberculosis and to the development of novel thioridazine analogs (15,30). The current first-line antibiotics are effective in the treatment of active tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

Nitrate Enhances the Survival of Mycobacterium tuberculosis during Inhibition of Respiration

Sohaskey

2008

J Bacteriol

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When oxygen is slowly depleted from growing cultures of Mycobacterium tuberculosis, they enter a state of nonreplicating persistence that resembles the dormant state seen with latent tuberculosis. In this hypoxic state, nitrate reductase activity is strongly induced. Nitrate in the medium had no effect on long-term persistence during gradual oxygen depletion (Wayne model) for up to 46 days, but significantly enhanced survival during sudden anaerobiosis. This enhancement required a functional nitrate reductase. Thioridazine is a member of the class of phenothiazines that act, in part, by inhibiting respiration. Thioridazine was toxic to both actively growing and nonreplicating cultures of M. tuberculosis. At a sublethal concentration of thioridazine, nitrate in the medium improved the growth. At lethal concentrations of thioridazine, nitrate increased survival during aerobic incubation as well as in microaerobic cultures that had just entered nonreplicating persistence (NRP-1). In contrast, the survival of anaerobic persistent (NRP-2) cultures exposed to thioridazine was not increased by the addition of nitrate. Nitrate reduction is proposed to play a role during the sudden interruption of aerobic respiration due to causes such as hypoxia, thioridazine, or nitric oxide.It has been estimated that over 2 billion people are infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (9). This is a staggering one-third of the world's population. Most of these infections are latent, showing no obvious symptoms. However, reactivation does occur and can progress to active disease. During latency, tubercle bacilli show increased resistance to many of the antibiotics that are used to treat active disease. There is a clear necessity to identify drugs that can target M. tuberculosis in this latent state. Understanding latency is important for the eventual control and eradication of tuberculosis.In the human host, tubercle bacilli reside in granulomas, structures that limit the availability of oxygen. This condition is reproduced in vitro by the Wayne model (27). Growing cultures of M. tuberculosis in sealed tubes gradually deplete the available oxygen and enter a microaerobic state called nonreplicating persistent stage 1 (NRP-1). This stage is characterized by the cessation of bacterial replication, a strong induction of respiratory nitrate reductase activity, and a change in energy metabolism (20,22,28). With further incubation, the oxygen levels continue to decrease until cultures enter the anaerobic stage, NRP-2. At this point, most RNA and protein synthesis has ceased and the bacteria are resistant to many antibiotics.One of the activities induced in M. tuberculosis during oxygen deprivation is the respiratory reduction of nitrate to nitrite. This activity provides energy for the bacteria entering the NRP state (28, 29). In culture, the induction of nitrate reductase activity is not due to an increase in the levels of the nitrate reductase enzyme encoded by narGHJI (22). Instead, hypoxia results in an...

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Section: Discussionmentioning

confidence: 99%

Nitrate Enhances the Survival of Mycobacterium tuberculosis during Inhibition of Respiration

Sohaskey

2008

J Bacteriol

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“…1), are a group of clinically relevant compounds that are predicted to target the ETC through inhibition of NDH-2 (18). THZ is an old neuroleptic agent that has demonstrated activity in killing drug-susceptible and drug-resistant M. tuberculosis in various model systems in vitro and ex vivo and in the murine model of TB infection (80)(81)(82)(83)(84). In the promising development, THZ demonstrated therapeutic benefit in treatment of XDR-TB patients in Argentina and is currently being used in trials in India (reviewed in reference 85).…”

Section: Drugs That Target the Etcmentioning

confidence: 99%

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Black

Warren

Louw

et al. 2014

Antimicrob Agents Chemother

117

102

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cThe inherent drug susceptibility of microorganisms is determined by multiple factors, including growth state, the rate of drug diffusion into and out of the cell, and the intrinsic vulnerability of drug targets with regard to the corresponding antimicrobial agent. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant source of global morbidity and mortality, further exacerbated by its ability to readily evolve drug resistance. It is well accepted that drug resistance in M. tuberculosis is driven by the acquisition of chromosomal mutations in genes encoding drug targets/promoter regions; however, a comprehensive description of the molecular mechanisms that fuel drug resistance in the clinical setting is currently lacking. In this context, there is a growing body of evidence suggesting that active extrusion of drugs from the cell is critical for drug tolerance. M. tuberculosis encodes representatives of a diverse range of multidrug transporters, many of which are dependent on the proton motive force (PMF) or the availability of ATP. This suggests that energy metabolism and ATP production through the PMF, which is established by the electron transport chain (ETC), are critical in determining the drug susceptibility of M. tuberculosis. In this review, we detail advances in the study of the mycobacterial ETC and highlight drugs that target various components of the ETC. We provide an overview of some of the efflux pumps present in M. tuberculosis and their association, if any, with drug transport and concomitant effects on drug resistance. The implications of inhibiting drug extrusion, through the use of efflux pump inhibitors, are also discussed.

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“…Thioridazine inhibits the growth of clinical isolates of M. tuberculosis that are resistant to streptomycin, rifampicin, isoniazid, ethambutol and pyrazinamide (first-line antituberculous drugs) [16]. The minimum inhibitory concentration of thioridazine required for 50% inhibition of M. tuberculosis H37Rv clinical isolates is 2.5 mg?mL -1 [17]. Because thioridazine does not appear toxic to the macrophage in vitro, it could be used in the treatment of intracellular M. tuberculosis infections [43].…”

Section: Phenothiazines: Thiorizadinementioning

confidence: 99%

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

et al. 2013

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Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis.A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012.We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, cotrimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.@ERSpublications Six antimicrobial drugs are not listed in WHO guidelines on MDR-TB treatment but could offer potential for TB treatment

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In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis

Cited by 63 publications

References 7 publications

Nitrate Enhances the Survival of Mycobacterium tuberculosis during Inhibition of Respiration

Nitrate Enhances the Survival of Mycobacterium tuberculosis during Inhibition of Respiration

Energy Metabolism and Drug Efflux in Mycobacterium tuberculosis

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

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