Effect of trifluoperazine, a potential drug for tuberculosis with psychotic disorders, on the growth of clinical isolates of drug resistant Mycobactehum tuberculosis

Dv, Gadre; Talwar,; Hc, Gupta; Ps, Murthy

doi:10.1097/00004850-199805000-00006

Cited by 25 publications

(18 citation statements)

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“…(35,52,58), and is known to accumulate in macrophages, enhancing its activity against intracellular pathogens. However, the bactericidal activity of TFP varies based on bacterial strain for various pathogens (35,52,59), which may account for why we observed no bactericidal effects for S. Typhimurium strain 14028 or Y. pestis ( Fig. 6B and 7B).…”

Section: Discussionmentioning

confidence: 87%

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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h Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

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Section: Discussionmentioning

confidence: 87%

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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“…Phenothiazines exert significant tuberculocidal activity against Mtb strains resistant to INH, rifampin, streptomycin, pyrazinamide, and ethambutol combined (21,22). TPZ is effective against virulent Mtb strain H 37 R v in a macrophage model of infection, and it is reported as synergistic with both INH and RIF (23,24).…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs

Weinstein

Yano²,

Li³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

252

292

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Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. Analysis of the Mtb genome predicts the existence of a branched aerobic respiratory chain terminating in a cytochrome bd system and a cytochrome aa3 system. Both chains can be initiated with type II NADH:menaquinone oxidoreductase. We present a detailed biochemical characterization of the aerobic respiratory chains from Mtb and show that phenothiazine analogs specifically inhibit NADH:menaquinone oxidoreductase activity. The emergence of drug-resistant strains of Mtb has prompted a search for antimycobacterial agents. Several phenothiazines analogs are highly tuberculocidal in vitro, suppress Mtb growth in a mouse model of acute infection, and represent lead compounds that may give rise to a class of selective antibiotics. Mycobacterium tuberculosis ͉ respiratory chainT he World Health Organization estimates that two billion people are infected with Mycobacterium tuberculosis (Mtb), and two million people die of the disease each year (1). Most individuals infected with the organism are latent carriers who have a 2-23% lifetime risk of developing reactivation tuberculosis (TB). The risk dramatically increases if the carrier's immune system is suppressed. Also, drug resistance is a serious concern; the isoniazid (INH)-resistance rate is Ϸ10%, and the rifampicin (RIF) resistance rate is Ϸ1%, with lower numbers in countries with effective TB programs and higher numbers in countries with deficient TB programs. The World Health Organization declared TB infections to be a global public health emergency (1), and the need to identify targets for antimicrobial therapy remains urgent.Mtb is capable of establishing persistent infection in the host by using a complex interplay between the host immune system and bacterial survival mechanisms. In the persistent infection, Mtb adapt to depletion of available oxygen and nutrients and enter a stage of nonreplicating persistence (NRP) in granulomatous or necrotic lesions. NRP Mtb are resistant to INH, ethambutol, and RIF, but they become sensitive to metronidazole in vitro (2). Given the critical role of oxygen in the generation of cellular energy and bacterial long-term survival, there is surprisingly little information on oxidative phosphorylation in Mtb. Clearly, oxidative phosphorylation is a central component in the production of ATP and the subsequent growth and pathogenesis of Mtb. Here, we characterize the aerobic respiratory pathway and show that NADH:menaquinone oxidoreductase (Ndh) is a key target for TB agents. Materials and MethodsMedia and Strains. Mtb H 37 R v was a gift from C. Imperatrice (Clinical Infectious Diseases, Hospital of the University of Pennsylvania) and Mycobacterium smegmatis Mc 2 155 was obtained from V. Mizrahi (National Health Laboratory Service, Johannesburg). Bacteria were cultured in 7H9 broth supplemented with 10% oleic acid-albumin-dextrose catalase͞0.5% glycerol͞0.05% Tween 80. Solid agar (15 g͞liter) was ad...

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“…[32] diphenhydramine (Alkyl amine) clofizamine bacteria [33,80] dye, steroid [120] tripolidine bacteria [63] (Phenyl piperadines) femoxetine enterobacteria (<400) a [47,79] paroxetine Enterococcus faecalis, Streptococcus progenes, Streptococcus pneumoniae cyproheptadine Plasmodium berghei, Plasmodium yoelii, Plasmodium falciparum [154] virus [73] Neuroleptics (Piperazines) prochlorperazine bacteria (25-200 mg/ml) a [72] Burkholderia pseudomalleus [180] (Thioxanthene) trifluoperazine Mycobacterium tuberculosis (5-32) a [79,81,84,85] Chlamydomonas spp. [178] Moloney leukemia virus [14] clopenthixol: [28,37,38,52,195] Diuretics amiloride Pseudomonas spp.…”

Section: Psychotherapeutics As Non-antibioticsmentioning

confidence: 99%

“…In vitro and In vivo Antimicrobial Potential of Non-antibiotics Many of the nonantibiotic compounds including dyes like methylene blue [1,54,101,117,152,171] and acridine [24,36,142]; atabrine [141]; chlorpromazine [11, 17, 22-27, 29, 31, 40, 54, 59, 61, 66, 76, 77, 93, 94, 98, 100, 102, 105, 106, 123, 124, 137, 165, 172-176], promazine [34,35], femoxetin [49], triflupromazine [70], promethazine [36,41,110,129,136,168], imipramine [177], trimiprime [55], prochlorperazine [100], thioridazine [83,88,90,156], thioxanthene clopenthixol [73,79,132] and flupenthixol [39,73]; TFP [14,81,84,85,178], aminoperazine [15], benzo-phenothiazine [16] and quinacrine [143]; antihistamines like diphenhydramine, bromodiphenhydramine [33,135], methdilazine [3,…”

Section: 6mentioning

confidence: 99%

“…[7,[75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92], Candida spp. [93][94][95], Amoeba proteus [96,97], P. falciparum [98][99][100][101], Leishmania donovani and Leishmania major [102][103][104][105][106][107], Trypanosoma [108][109][110] and helminths [111] in vitro and in vivo [2, 3, 19, 23, 26, 41, 49, 51, 53, 56, 61, 67-69, 71-74, 77, 82-89, 91, 105, 108, 109] by altering the permeability of the microbial cell membrane [2, 3, 18-20, 23, 25, 27, 30, 34, 38-40, 46, 54, 59, 60, 79, 81, 95, 101-103, 107, 112] and enhance the in vitro and in vivo activity of certain antibiotics against specific bacteria [2,18,39,128,130] to make antibiotic-resistant bacteria susceptible to the previously used antibiotics …”

Section: 6mentioning

confidence: 99%

See 1 more Smart Citation

Non‐Antibiotics – An Alternative for Microbial Resistance: Scope and Hope

Chattopadhyay

Das

Patra

et al. 2008

New Strategies Combating Bacterial Infection

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The antimicrobial activity of non-chemotherapeutic compounds, such as methylene blue, phenothiazine, thioxanthene and related agents, has been known since the time of Paul Ehrlich . In this context the term nonantibiotics was introduced to include a variety of compounds used in the management of pathological conditions of noninfectious etiology. Despite the availability of hundreds of anti-infective drugs the emergence of antibiotic resistance and new infectious agents create the therapeutic challenge to the medical community. Hence, the search for newer agents to tackle the global problem is continuing. It has been noted that many of the phenothiazines,

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Effect of trifluoperazine, a potential drug for tuberculosis with psychotic disorders, on the growth of clinical isolates of drug resistant Mycobactehum tuberculosis

Cited by 25 publications

References 0 publications

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs

Non‐Antibiotics – An Alternative for Microbial Resistance: Scope and Hope

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