Lansoprazole is an antituberculous prodrug targeting cytochrome bc1

Rybniker, Jan; Vocat, Anthony; Sala, Claudia; Busso, Philippe; Pojer, Florence; Benjak, Andrej; Cole, Stewart T.

doi:10.1038/ncomms8659

Cited by 153 publications

(191 citation statements)

References 23 publications

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“…As an example, with M. tuberculosis, it has recently been shown that the heartburn/proton pump inhibitor drug lansoprazole is metabolized to lansoprazole sulfide (structures in Fig. 6), which has potent activity against M. tuberculosis inside macrophages (85), and similar antibacterial effects are seen with omeprazole (which is reduced to the active sulfide) in Helicobacter pylori (86), as well as with rabeprazole (87,88). Lansoprazole, omeprazole, and rabeprazole are all proton pump inhibitors that contain benzimidazole groups with sulfoxide substituents.…”

Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

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

147

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

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

147

169

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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%

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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“…Generation of point mutations in M. tuberculosis H37Rv was done by a recombineering method (20,21). H37Rv/pJV53 was grown to log phase (OD 600 of 0.5) in 7H9 medium containing 25 g/ml of kanamycin before being induced with 0.2% acetamide overnight.…”

Section: Methodsmentioning

confidence: 99%

Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis

Foo

Lechartier

Kolly

et al. 2016

Antimicrob Agents Chemother

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dBenzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-D-ribose oxidase (DprE1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. To probe the role of C387, we used promiscuous site-directed mutagenesis to introduce other codons at this position into dprE1 of M. tuberculosis. The resultant viable BTZ-resistant mutants were characterized in vitro, ex vivo, and biochemically to gain insight into the effects of these mutations on DprE1 function and on M. tuberculosis. Five different mutations (C387G, C387A, C387S, C387N, and C387T) conferred various levels of resistance to BTZ and exhibited different phenotypes. The C387G and C387N mutations resulted in a lower growth rate of the mycobacterium on solid medium, which could be attributed to the significant decrease in the catalytic efficiency of the DprE1 enzyme. All five mutations rendered the mycobacterium less cytotoxic to macrophages. Finally, differences in the potencies of covalent and noncovalent DprE1 inhibitors in the presence of C387 mutations were revealed by enzymatic assays. As expected from the mechanism of action, the covalent inhibitor PBTZ169 only partially inhibited the mutant DprE1 enzymes compared to the near-complete inhibition with a noncovalent DprE1 inhibitor, Ty38c. This study emphasizes the importance of the C387 residue for DprE1 activity and for the killing action of covalent inhibitors such as BTZs and other recently identified nitroaromatic inhibitors. Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease which is a leading cause of death worldwide and poses a major threat to global health. The World Health Organization estimates that in 2014, 9.6 million people contracted TB, and 1.5 million people died (1). In addition, the emergence and worldwide spread of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are alarming. With MDR-TB strains being resistant to the frontline drugs isoniazid and rifampin and XDR-TB strains being resistant to frontline and additionally second-line drugs, there is an urgent need for new drugs for TB.1,3-Benzothiazin-4-ones (BTZs) were discovered in 2009, with the lead compound BTZ043 having high potency (MIC of 1 ng/l) against M. tuberculosis strain H37Rv (2) and demonstrating efficacy against MDR and XDR clinical isolates (3). Piperazine-containing BTZ (PBTZ) derivatives were then designed with improved pharmacological properties (4), and the optimized lead compound PBTZ169 is currently in clinical trials (5).Genetic analysis of resistant mutants and enzymology have identified the target of BTZs as decaprenylphosphoryl-␤-D-ribose oxidase (DprE1), an essential flavoenzyme in M. tuberculosis involved in cell wall synthesis (2). DprE1 acts in concert with DprE2 to catalyze ...

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Lansoprazole is an antituberculous prodrug targeting cytochrome bc1

Cited by 153 publications

References 23 publications

Antiinfectives targeting enzymes and the proton motive force

Antiinfectives targeting enzymes and the proton motive force

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

Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis

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