Activity of Trifluoperazine against Replicating, Non-Replicating and Drug Resistant M. tuberculosis

Advani, Meeta J.; Siddiqui, Imran; Sharma, Pawan; Reddy, Hemalatha

doi:10.1371/journal.pone.0044245

Cited by 23 publications

(19 citation statements)

References 39 publications

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“…Some drugs identified in in vitro screens have previously been shown to have some antimicrobial activity, such as TFP and proton pump inhibitors, such as pantoprazole, which are known antituberculars (52,53). After validating that none of the 58 drugs from the more clinically relevant posttreatment Growth was continued at 28°C for 2 h, followed by a temperature shift to 37°C for an additional 3 h of incubation.…”

Section: Discussionmentioning

confidence: 99%

“…TFP is a known antimycobacterial, has been shown to have bactericidal properties against several pathogens, including staphylococci, vibrios, Salmonella, and Pseudomonas spp. (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.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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: 99%

Section: Discussionmentioning

confidence: 99%

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

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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“…The phenothioazines thioridazine and trifluoperazine (compound 94) target the electron transport chain, disrupt membrane potential, and ultimately decrease ATP levels (275). Trifluoperazine was bactericidal to M. tuberculosis that was nonreplicating when cultured at acidic pH, in nutrient starved cultures, or at neutral pH in the presence of the nitric oxide donor DETA-NO (275). As described in the section on quinolines, TMC207 targets ATP synthase (AtpE, encoded by rv1305).…”

Section: Membrane Depolarizers-mentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

Gold

Nathan

2017

Tuberculosis and the Tubercle Bacillus

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycinaddicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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“…The bactericidal action of clofazimine is reversed by addition of menaquinone-4 (MK-4) (273, 274). The phenothioazines thioridazine and trifluoperazine ( compound 94 ) target the electron transport chain, disrupt membrane potential, and ultimately decrease ATP levels (275). Trifluoperazine was bactericidal to M. tuberculosis that was nonreplicating when cultured at acidic pH, in nutrient starved cultures, or at neutral pH in the presence of the nitric oxide donor DETA-NO (275).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

“…The phenothioazines thioridazine and trifluoperazine ( compound 94 ) target the electron transport chain, disrupt membrane potential, and ultimately decrease ATP levels (275). Trifluoperazine was bactericidal to M. tuberculosis that was nonreplicating when cultured at acidic pH, in nutrient starved cultures, or at neutral pH in the presence of the nitric oxide donor DETA-NO (275). As described in the section on quinolines, TMC207 targets ATP synthase (AtpE, encoded by rv1305 ).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

View full text Add to dashboard Cite

While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

show abstract

Activity of Trifluoperazine against Replicating, Non-Replicating and Drug Resistant M. tuberculosis

Cited by 23 publications

References 39 publications

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

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

Targeting Phenotypically TolerantMycobacterium tuberculosis

Targeting Phenotypically TolerantMycobacterium tuberculosis

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