scholarly journals Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid

2003 ◽  
Vol 52 (5) ◽  
pp. 790-795 ◽  
Author(s):  
Y. Zhang
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Membrane Transport ◽  
Mode Of Action ◽  
Pyrazinoic Acid

scholarly journals Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Yumeng Zhang ◽  
Jia Zhang ◽  
Peng Cui ◽  
Ying Zhang ◽  
Wenhong Zhang
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Binding Studies ◽  
Content Type ◽  
Clinical Strains ◽  
Efflux Pump Inhibitors ◽  
Level Resistance ◽  
Pyrazinoic Acid ◽  
Increased Susceptibility ◽  
Efflux Proteins

ABSTRACT Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the pncA gene. Although resistance to PZA is mostly caused by pncA mutations and less commonly by rpsA, panD, and clpC1 mutations, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in Mycobacterium tuberculosis previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with an M. tuberculosis proteome microarray and identified four efflux proteins (Rv0191, Rv3756c, Rv3008, and Rv1667c) that bind POA. Overexpression of the four efflux pump genes in M. tuberculosis caused low-level resistance to PZA and POA but not to other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine, and verapamil caused increased susceptibility to PZA in M. tuberculosis strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA/POA efflux and cause PZA resistance in M. tuberculosis. Future studies are needed to assess their roles in PZA resistance in clinical strains.

scholarly journals Stereocontrolled Total Synthesis of Muraymycin D1 Having a Dual Mode of Action against Mycobacterium tuberculosis

2016 ◽  
Vol 138 (39) ◽  
pp. 12975-12980 ◽  
Author(s):  
Katsuhiko Mitachi ◽  
Bilal A. Aleiwi ◽  
Christopher M. Schneider ◽  
Shajila Siricilla ◽  
Michio Kurosu
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Total Synthesis ◽  
Mode Of Action ◽  
Dual Mode

scholarly journals Mycobacterium tuberculosis ribosomal protein S1 (RpsA) and variants with truncated C-terminal end show absence of interaction with pyrazinoic acid

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Katherine Vallejos-Sánchez ◽  
Juan M. Lopez ◽  
Ricardo Antiparra ◽  
Emily Toscano ◽  
Harry Saavedra ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ribosomal Protein ◽  
Ribosomal Protein S1 ◽  
Pyrazinoic Acid

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

scholarly journals Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis

2018 ◽  
Vol 72 (2) ◽  
pp. 263-274.e5 ◽  
Author(s):  
Hamed Mosaei ◽  
Vadim Molodtsov ◽  
Bernhard Kepplinger ◽  
John Harbottle ◽  
Christopher William Moon ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Mode Of Action

scholarly journals A Flow Cytometry Method for Rapidly Assessing Mycobacterium tuberculosis Responses to Antibiotics with Different Modes of Action

2016 ◽  
Vol 60 (7) ◽  
pp. 3869-3883 ◽  
Author(s):  
Charlotte Louise Hendon-Dunn ◽  
Kathryn Sarah Doris ◽  
Stephen Richard Thomas ◽  
Jonathan Charles Allnutt ◽  
Alice Ann Neville Marriott ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mycobacterium Tuberculosis ◽  
Mode Of Action ◽  
Ester Group ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Additional Advantage ◽  
Content Type ◽  
Fluorescent Marker ◽  
Sytox Green

ABSTRACTCurrent methods for assessing the drug susceptibility ofMycobacterium tuberculosisare lengthy and do not capture information about viable organisms that are not immediately culturable under standard laboratory conditions as a result of antibiotic exposure. We have developed a rapid dual-fluorescence flow cytometry method using markers for cell viability and death. We show that the fluorescent marker calcein violet with an acetoxy-methyl ester group (CV-AM) can differentiate between populations ofM. tuberculosisgrowing at different rates, while Sytox green (SG) can differentiate between live and dead mycobacteria.M. tuberculosiswas exposed to isoniazid or rifampin at different concentrations over time and either dual stained with CV-AM and SG and analyzed by flow cytometry or plated to determine the viability of the cells. Although similar trends in the loss of viability were observed when the results of flow cytometry and the plate counting methods were compared, there was a lack of correlation between these two approaches, as the flow cytometry analysis potentially captured information about cell populations that were unable to grow under standard conditions. The flow cytometry approach had an additional advantage in that it could provide insights into the mode of action of the drug: antibiotics targeting the cell wall gave a flow cytometry profile distinct from those inhibiting intracellular processes. This rapid drug susceptibility testing method could identify more effective antimycobacterials, provide information about their potential mode of action, and accelerate their progress to the clinic.

scholarly journals Metallochaperones Are Needed for Mycobacterium tuberculosis and Escherichia coli Nicotinamidase-Pyrazinamidase Activity

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Patricia Sheen ◽  
Anuntxi Monsalve ◽  
Jhanina Campos ◽  
Rodolfo Huerta ◽  
Ricardo Antiparra ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Mycobacterium Tuberculosis ◽  
Reference Strain ◽  
Mechanisms Of Action ◽  
Efflux Rate ◽  
Content Type ◽  
Causes Of Disease ◽  
Pyrazinoic Acid

ABSTRACT Mycobacterium tuberculosis nicotinamidase-pyrazinamidase (PZAse) is a metalloenzyme that catalyzes conversion of nicotinamide-pyrazinamide to nicotinic acid-pyrazinoic acid. This study investigated whether a metallochaperone is required for optimal PZAse activity. M. tuberculosis and Escherichia coli PZAses (PZAse-MT and PZAse-EC, respectively) were inactivated by metal depletion (giving PZAse-MT–Apo and PZAse-EC–Apo). Reactivation with the E. coli metallochaperone ZnuA or Rv2059 (the M. tuberculosis analog) was measured. This was repeated following proteolytic and thermal treatment of ZnuA and Rv2059. The CDC1551 M. tuberculosis reference strain had the Rv2059 coding gene knocked out, and PZA susceptibility and the pyrazinoic acid (POA) efflux rate were measured. ZnuA (200 μM) achieved 65% PZAse-EC–Apo reactivation. Rv2059 (1 μM) and ZnuA (1 μM) achieved 69% and 34.3% PZAse-MT–Apo reactivation, respectively. Proteolytic treatment of ZnuA and Rv2059 and application of three (but not one) thermal shocks to ZnuA significantly reduced the capacity to reactivate PZAse-MT–Apo. An M. tuberculosis Rv2059 knockout strain was Wayne positive and susceptible to PZA and did not have a significantly different POA efflux rate than the reference strain, although a trend toward a lower efflux rate was observed after knockout. The metallochaperone Rv2059 restored the activity of metal-depleted PZAse in vitro. Although Rv2059 is important in vitro, it seems to have a smaller effect on PZA susceptibility in vivo. It may be important to mechanisms of action and resistance to pyrazinamide in M. tuberculosis. Further studies are needed for confirmation. IMPORTANCE Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis and remains one of the major causes of disease and death worldwide. Pyrazinamide is a key drug used in the treatment of tuberculosis, yet its mechanism of action is not fully understood, and testing strains of M. tuberculosis for pyrazinamide resistance is not easy with the tools that are presently available. The significance of the present research is that a metallochaperone-like protein may be crucial to pyrazinamide’s mechanisms of action and of resistance. This may support the development of improved tools to detect pyrazinamide resistance, which would have significant implications for the clinical management of patients with tuberculosis: drug regimens that are appropriately tailored to the resistance profile of a patient’s individual strain lead to better clinical outcomes, reduced onward transmission of infection, and reduction of the development of resistant strains that are more challenging and expensive to treat.

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