scholarly journals Activity of the Fluoroquinolone DC-159a in the Initial and Continuation Phases of Treatment of Murine Tuberculosis

2011 ◽  
Vol 55 (4) ◽  
pp. 1781-1783 ◽  
Author(s):  
Zahoor Ahmad ◽  
Austin Minkowski ◽  
Charles A. Peloquin ◽  
Kathy N. Williams ◽  
Khisimuzi E. Mdluli ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Murine Model ◽  
Drug Combinations ◽  
Preclinical Evaluation ◽  
Resistant Tuberculosis

ABSTRACTDC-159a is a new fluoroquinolone with more potentin vitroactivity than available fluoroquinolones against both drug-susceptible and fluoroquinolone-resistantMycobacterium tuberculosis. Here, we report that DC-159a displays pharmacokinetics similar to those of moxifloxacin yet is more active than moxifloxacin during both the initial and continuation phases of treatment in a murine model. These results warrant further preclinical evaluation of DC-159a in selected drug combinations against drug-susceptible and fluoroquinolone-resistant tuberculosis.

scholarly journals Sulfamethoxazole Susceptibility of Mycobacterium tuberculosis Isolates from HIV-Infected Ugandan Adults with Tuberculosis Taking Trimethoprim-Sulfamethoxazole Prophylaxis

2015 ◽  
Vol 59 (9) ◽  
pp. 5844-5846 ◽  
Author(s):  
Sam Ogwang ◽  
Caryn E. Good ◽  
Brenda Okware ◽  
Mary Nsereko ◽  
Michael R. Jacobs ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Pulmonary Tb ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Sub Saharan

ABSTRACTAdditional drugs are needed for the treatment of multidrug-resistant tuberculosis (TB). Sulfamethoxazole has been shown to havein vitroactivity againstMycobacterium tuberculosis; however, there is concern about resistance given the widespread use of trimethoprim-sulfamethoxazole prophylaxis among HIV-infected patients in sub-Saharan Africa. Thirty-eight of 40Mycobacterium tuberculosisisolates (95%) from pretreatment sputum samples from Ugandan adults with pulmonary TB, including HIV-infected patients taking trimethoprim-sulfamethoxazole prophylaxis, were susceptible with MICs of ≤38.4 μg/ml.

scholarly journals Importance of Confirming Data on theIn VivoEfficacy of Novel Antibacterial Drug Regimens against Various Strains of Mycobacterium tuberculosis

2011 ◽  
Vol 56 (2) ◽  
pp. 731-738 ◽  
Author(s):  
Mary A. De Groote ◽  
Veronica Gruppo ◽  
Lisa K. Woolhiser ◽  
Ian M. Orme ◽  
Janet C. Gilliland ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Studies ◽  
Strain Difference ◽  
Drug Combinations ◽  
Antibacterial Drug ◽  
Preclinical Testing ◽  
Content Type ◽  
Drug Regimens

ABSTRACTIn preclinical testing of antituberculosis drugs, laboratory-adapted strains ofMycobacterium tuberculosisare usually used both forin vitroandin vivostudies. However, it is unknown whether the heterogeneity ofM. tuberculosisstocks used by various laboratories can result in different outcomes in tests of antituberculosis drug regimens in animal infection models. In head-to-head studies, we investigated whether bactericidal efficacy results in BALB/c mice infected by inhalation with the laboratory-adapted strains H37Rv and Erdman differ from each other and from those obtained with clinical tuberculosis strains. Treatment of mice consisted of dual and triple drug combinations of isoniazid (H), rifampin (R), and pyrazinamide (Z). The results showed that not all strains gave the samein vivoefficacy results for the drug combinations tested. Moreover, the ranking of HRZ and RZ efficacy results was not the same for the two H37Rv strains evaluated. The magnitude of this strain difference also varied between experiments, emphasizing the risk of drawing firm conclusions for human trials based on single animal studies. The results also confirmed that the antagonism seen within the standard HRZ regimen by some investigators appears to be anM. tuberculosisstrain-specific phenomenon. In conclusion, the specific identity ofM. tuberculosisstrain used was found to be an important variable that can change the apparent outcome ofin vivoefficacy studies in mice. We highly recommend confirmation of efficacy results in late preclinical testing against a differentM. tuberculosisstrain than the one used in the initial mouse efficacy study, thereby increasing confidence to advance potent drug regimens to clinical trials.

scholarly journals Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4457-4463 ◽  
Author(s):  
Benoit Lechartier ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Drug Resistant Strains ◽  
Transfer Chain

ABSTRACTClofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. InMycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM againstM. tuberculosisand found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergisticin vitrowith benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was testedin vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains ofM. tuberculosis.

scholarly journals In VitroandIn VivoActivities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

2014 ◽  
Vol 59 (1) ◽  
pp. 136-144 ◽  
Author(s):  
A. M. Upton ◽  
S. Cho ◽  
T. J. Yang ◽  
Y. Kim ◽  
Y. Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Drug Resistant ◽  
Next Generation ◽  
Content Type ◽  
Resistant Tuberculosis

ABSTRACTNitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 againstMycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidalin vitroagainst replicating and nonreplicatingMycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity againstMycobacterium tuberculosisH37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7.In vitrostudies andin vivostudies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life.In vitrostudies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependentin vivobactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

scholarly journals Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.

2021 ◽  
Author(s):  
Yu Wei ◽  
Buhari Yusuf ◽  
Wang Shuai ◽  
Tian Xirong ◽  
H. M. Adnan Hameed ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Drug Combinations ◽  
Bacterial Burden ◽  
Injectable Drug ◽  
Drug Candidates ◽  
Stopping Treatment ◽  
Fast Acting

Toxicity and inconvenience associated with the use of injectable drug-containing regimens for tuberculosis (TB) have made all-oral regimens a preferred alternative. Widespread resistance to fluoroquinolones and pyrazinamide makes it essential to identify new drug candidates and study their effects on current regimens for TB. TB47 is a pyrazolo[1,5-a]pyridine-3-carboxamide with powerful synergistic in vitro and in vivo activities against mycobacteria, especially with clofazimine. Here, we investigated the bactericidal and sterilizing activities of novel oral regimens containing TB47 + clofazimine + linezolid, and the potential roles of levofloxacin and/or pyrazinamide in such drug combinations. Using a well-established mouse model, we assessed the effect of these regimens on bacterial burden in the lung during treatment and relapse (4 months after stopping treatment + immunosuppression). Our findings indicate that the TB47 + clofazimine + linezolid + pyrazinamide, with/without levofloxacin, regimens had fast-acting (4 months) sterilizing activity and no relapse was observed. When pyrazinamide was excluded from the regimen, treatment times were longer (5-6 months) to achieve sterilizing conditions. We propose that TB47 + clofazimine + linezolid can form a highly sterilizing block for use as an alternative pan-TB regimen.

scholarly journals Bactericidal action of ofloxacin, sulbactam-ampicillin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis.

1996 ◽  
Vol 40 (10) ◽  
pp. 2296-2299 ◽  
Author(s):  
D Herbert ◽  
C N Paramasivan ◽  
P Venkatesan ◽  
G Kubendiran ◽  
R Prabhakar ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Stationary Phase ◽  
Bactericidal Activity ◽  
Exponential Phase ◽  
Drug Combinations ◽  
Bactericidal Action ◽  
Level Of Activity ◽  
Susceptible Isolate ◽  
Emergence Of Resistance

The bactericidal actions of ofloxacin and sulbactam-ampicillin, alone and in combination with rifampin and isoniazid, on exponential-phase and stationary-phase cultures of a drug-susceptible isolate of Mycobacterium tuberculosis were studied in vitro. In exponential-phase cultures, all drugs were bactericidal, with the higher concentrations of ofloxacin (5 micrograms/ml) and sulbactam-ampicillin (15 micrograms of ampicillin per ml) being as bactericidal as 1 microgram of isoniazid per ml or 1 microgram of rifampin per ml. In two-drug combinations, both drugs increased the levels of activity of isoniazid and rifampin and were almost as bactericidal as isoniazid-rifampin; they also appeared to increase the level of activity of isoniazid-rifampin in three-drug combinations. In contrast, ofloxacin and sulbactam-ampicillin had little bactericidal activity against stationary-phase cultures and were less active than isoniazid or rifampin alone. Furthermore, in two-drug or three-drug combinations, they did not increase the level of activity of isoniazid, rifampin, or isoniazid-rifampin. These findings suggest that ofloxacin and sulbactam-ampicillin are likely to be most useful in the early stages of treatment and in preventing the emergence of resistance to other drugs but are unlikely to be effective as sterilizing drugs helping to kill persisting lesional bacilli.

scholarly journals Toxin-Activating Stapled Peptides Discovered by Structural Analysis Were Identified as New Therapeutic Candidates That Trigger Antibacterial Activity against Mycobacterium tuberculosis in the Mycobacterium smegmatis Model

2021 ◽  
Vol 9 (3) ◽  
pp. 568
Author(s):  
Sung-Min Kang ◽  
Heejo Moon ◽  
Sang-Woo Han ◽  
Byeong Wook Kim ◽  
Do-Hee Kim ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimicrobial Agents ◽  
Structural Information ◽  
Multidrug Resistant ◽  
Cell Permeability ◽  
Bacterial Cells ◽  
New Era ◽  
Resistant Tuberculosis ◽  
Α Helix

The structure-function relationships of toxin-antitoxin (TA) systems from Mycobacterium tuberculosis have prompted the development of novel and effective antimicrobial agents that selectively target this organism. The artificial activation of toxins by peptide inhibitors can lead to the growth arrest and eventual death of bacterial cells. Optimizing candidate peptides by hydrocarbon α-helix stapling based on structural information from the VapBC TA system and in vitro systematic validation led to V26-SP-8, a VapC26 activator of M. tuberculosis. This compound exhibited highly enhanced activity and cell permeability owing to the stabilizing helical propensity of the peptide. These characteristics will increase its efficacy against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Similar approaches utilizing structural and biochemical information for new antibiotic targets opens a new era for developing TB therapies.

scholarly journals In Vitro Activity of Tetracycline Analogs against Multidrug-resistant and Extensive drug resistance Clinical Isolates of Mycobacterium tuberculosis

2019 ◽  
Author(s):  
Qi Ouyang ◽  
Dachuan Lin ◽  
Guofang Deng ◽  
Zhihua Wen ◽  
Houming Liu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Underlying Mechanism ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Ammonium Bromide ◽  
Resistant Tuberculosis ◽  
Mdr Tb

Abstract Background Multidrug-resistant tuberculosis (MDR-TB) has become a big threaten to global health . The current strategy for treatment of MDR-TB and extensive drug resistant tuberculosis (XDR-TB) is with low efficacy and high side effect. While new drug is fundamental for cure MDR-TB, repurposing the Food and Drug Administration (FDA)-approved drugs represents an alternative soluation with less cost.Methods The activity of 8 tetracycline-class antibiotics against mycobacterium tuberculosis ( M.tb ) were determined by Minimum Inhibitory Concentration (MIC) in vitro. A transposon M.smeg libraries was generated by using the Harm phage and then used to isolate the conditional growth mutants in doxycycline containing plate. 11 mutants were isolated and genomic DNAs were extracted using the cetyltrimethyl ammonium bromide (CTAB) method and analyzed by whole genome sequencing.Results We found that three of eight drugs efficiently inhibited mycobacteria growth under the peak plasma concentration in the human body. Further tests showed these three tetracycline analogs (demeclocycline, doxycycline and methacycline) had antimicrobial activity against seven clinical isolates, including MDR and XDR strains. Among them, Doxycycline had the lowest MICs in all mycobacteria strains tested in this study. By using a transposon library, we identify the insertion of transposon in two genes, porin and MshA, associate with the resistant to doxycycline.Conclusions Our findings show that tetracycline analogs such as doxycycline, has bactericidal activity against not only drug sensitive M.tb , but also clinical MDR and XDR strains, provided proof of concept to repurpose doxycycline to fight MDR-TB and XDR-TB. Further investigations are warranted to clarify the underlying mechanism and optimize the strategy in combination with other anti-TB drugs.

In vitro effect of three-drug combinations of antituberculous agents against multidrug-resistant Mycobacterium tuberculosis isolates

2013 ◽  
Vol 41 (3) ◽  
pp. 278-280 ◽  
Author(s):  
Emma Rey-Jurado ◽  
Griselda Tudó ◽  
Jorge Puig de la Bellacasa ◽  
Mateu Espasa ◽  
Julian González-Martín
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Drug Combinations ◽  
Vitro Effect

scholarly journals Sterilizing Activities of Novel Combinations Lacking First- and Second-Line Drugs in a Murine Model of Tuberculosis

2012 ◽  
Vol 56 (6) ◽  
pp. 3114-3120 ◽  
Author(s):  
Kathy Williams ◽  
Austin Minkowski ◽  
Opokua Amoabeng ◽  
Charles A. Peloquin ◽  
Dinesh Taylor ◽  
...  
Keyword(s):  
Murine Model ◽  
Rank Order ◽  
Building Blocks ◽  
Drug Combinations ◽  
New Drugs ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Duration Of Treatment ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis

ABSTRACTNovel oral regimens composed of new drugs with potent activity againstMycobacterium tuberculosisand no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

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