Aminopyrazinamides: Novel and Specific GyrB Inhibitors that Kill Replicating and Nonreplicating <i>Mycobacterium tuberculosis</i>

Shirude, Pravin S.; Madhavapeddi, Prashanti; Tucker, J.A.; Murugan, K; Patil, Vikas; Basavarajappa, Halesha D.; Raichurkar, Anandkumar; Humnabadkar, Vaishali; Hussein, Syeed; Sharma, Sreevalli; Ramya, V.; Narayan, Chandan; Balganesh, Tanjore S.; Sambandamurthy, Vasan K.

doi:10.1021/cb300510w

Cited by 77 publications

(84 citation statements)

References 12 publications

(28 reference statements)

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“…We determined the MIC of AZD5847 by a standard microdilution method as described earlier (16). The assay was performed in duplicate 96-well microtiter plates (Tarsons, Kolkata, India) in which all peripheral wells were filled with sterile distilled water.…”

Section: Methodsmentioning

confidence: 99%

Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

Balasubramanian

Solapure

Iyer

et al. 2014

Antimicrob Agents Chemother

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Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials.T uberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose an enormous threat to global public health (1). In 2010, nearly 9 million people were infected with M. tuberculosis and 1.4 million died from the disease (1, 2). While the vast majority of cases of drug-sensitive TB are curable with appropriate drug therapy, rates of treatment success have stagnated due to the long duration and complexity of therapy and the rising incidence of drug resistance (1, 3, 4). Standard TB therapy alone involves four drugs taken for at least 6 months, and treatment for multidrugresistant (MDR) and extensively drug-resistant (XDR) TB requires administration of more toxic antibiotics-including at least one injectable-for durations of 1 to 2 years (5). Often, patients are coinfected with HIV, which further complicates treatment due to deleterious potential drug-drug interactions between TB medications and antiretrovirals (6). Despite the limitations of current treatment options, only one new class of TB drugs has been approved in the past 40 years (7). There is an urgent need for new TB drugs with greater efficacy, reduced toxicities, and improved compatibility with antiretrovirals.Recent evidence demonstrates that linezolid, the only member of the oxazolidinone class of antimicrobials currently on the market, has efficacy against MDR TB (8-11). The potential of linezolid for the treatment of TB is limited due to the incidence of serious adverse effects, including cytopenias, neuropathies, lactic acidosis, and rhabdomyolysis (12, 13). Risk increases with increasing dose and duration, which is particularly problematic, given the typical extended course of chemotherapy for TB. A numbe...

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Section: Methodsmentioning

confidence: 99%

Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

Balasubramanian

Solapure

Iyer

et al. 2014

Antimicrob Agents Chemother

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“…The catalytic subunits (GyrA/ParC) are clinically validated drug targets of the fluoroquinolones, such as moxifloxacin (MXF) (2), while the ATPase subunits (GyrB/ParE) have not been as extensively exploited and may present a new option for treating DR strains of M. tuberculosis (3). Furthermore, several different chemical classes have been described as inhibitors of gyrase B with potent activity against DR bacteria, including M. tuberculosis (4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Locher

Jones

Hanzelka

et al. 2015

Antimicrob Agents Chemother

101

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dNew drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drugresistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 g/ml and 0.08 to 5.48 g/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 g/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 g/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.

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“…In the past few decades, these designs have led to the development of successful drug molecules including dorzolamide, imatinib and raltegravir [9][10][11][12][13][14] . Although various valuable crystal structures of the DNA gyrase of MT have been proposed to enlighten its working mechanism [15][16][17] , none has so far demonstrated the interaction between major inhibitor novobiocin and the catalytic domain (ATPase) of GyrB. Previously, we designed a homology model of MT DNA GyrB ATPase active site using the crystal structure of the 43K ATPase domain of Thermus thermophilus gyrase B in complex with novobiocin (RSCB Pdb id; 1KIJ) as a template and maintaining novobiocin and water in the hydrophobic pocket, which are assumed to be important for the ligand activity 18 .…”

mentioning

confidence: 99%

Molecular Modelling and Activity Analysis of Mycobacterium tuberculosis DNA Gyrase B ATPase Active Site

Berk¹,

Şahin²

2017

actapharm

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Aminopyrazinamides: Novel and Specific GyrB Inhibitors that Kill Replicating and Nonreplicating Mycobacterium tuberculosis

Cited by 77 publications

References 12 publications

Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Molecular Modelling and Activity Analysis of Mycobacterium tuberculosis DNA Gyrase B ATPase Active Site

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