Determination of Minimum Inhibitory Concentration of Cycloserine in Multidrug Resistant Mycobacterium Tuberculosis Isolates

Singh, Rishan

doi:10.12816/0008228

Cited by 5 publications

(7 citation statements)

References 2 publications

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“…Previous studies on wild-type M. tuberculosis found MIC values for DCS equal to 15 μ g/mL, 18 while MDR-TB clinical isolates exhibited MIC values ranging from 32 to 64 μ g/mL. 37 In general, laboratory strains are more susceptible to antibiotics than clinically isolated strains, such as MDR-TB strains. Similar experiments revealed that LCS exhibits a ∼10-fold better inhibitory growth effect than DCS, with a MIC value of 0.3 μ g/mL (Table S1).…”

Section: Resultsmentioning

confidence: 94%

Mechanism-Based Inhibition of the Mycobacterium tuberculosis Branched-Chain Aminotransferase by d- and l-Cycloserine

et al. 2017

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The branched-chain aminotransferase is a pyridoxal 5′-phosphate (PLP)-dependent enzyme responsible for the final step in the biosynthesis of all three branched-chain amino acids, L-leucine, L-isoleucine, and L-valine, in bacteria. We have investigated the mechanism of inactivation of the branched-chain aminotransferase from Mycobacterium tuberculosis (MtIlvE) by D- and L-cycloserine. D-Cycloserine is currently used only in the treatment of multidrug–drug-resistant tuberculosis. Our results show a time-and concentration-dependent inactivation of MtIlvE by both isomers, with L-cycloserine being a 40-fold better inhibitor of the enzyme. Minimum inhibitory concentration (MIC) studies revealed that L-cycloserine is a 10-fold better inhibitor of Mycobacterium tuberculosis growth than D-cycloserine. In addition, we have crystallized the MtIlvE-D-cycloserine inhibited enzyme, determining the structure to 1.7 Å. The structure of the covalent D-cycloserine-PMP adduct bound to MtIlvE reveals that the D-cycloserine ring is planar and aromatic, as previously observed for other enzyme systems. Mass spectrometry reveals that both the D-cycloserine- and L-cycloserine-PMP complexes have the same mass, and are likely to be the same aromatized, isoxazole product. However, the kinetics of formation of the MtIlvE D-cycloserine-PMP and MtIlvE L-cycloserine-PMP adducts are quite different. While the kinetics of the formation of the MtIlvE D-cycloserine-PMP complex can be fit to a single exponential, the formation of the MtIlvE L-cycloserine-PMP complex occurs in two steps. We propose a chemical mechanism for the inactivation of D- and L-cycloserine which suggests a stereochemically determined structural role for the differing kinetics of inactivation. These results demonstrate that the mechanism of action of D-cycloserine’s activity against M. tuberculosis may be more complicated than previously thought and that D-cycloserine may compromise the in vivo activity of multiple PLP-dependent enzymes, including MtIlvE.

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Section: Resultsmentioning

confidence: 94%

Mechanism-Based Inhibition of the Mycobacterium tuberculosis Branched-Chain Aminotransferase by d- and l-Cycloserine

et al. 2017

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“…The mean number of drugs (percentage coefficient of variation) detected at each lung cavity position was 3.0 (59.0%), whereas those above lower limit of quantitation were 2.8 (64.8%) (drugs shown in Figure E4). The mean number of drugs with effective concentrations above the lowest MIC in epidemiologic study distributions reported in the literature fell to 2.1 (70.6%) drugs (P , 0.01), shown by cavity position in Figure 1H (24,30,(36)(37)(38). Because all patients were receiving at least eight drugs, this means that penetration into the cavity was highly variable.…”

Section: Cavity Dissection and Drug Concentrations In Lung Cavitiesmentioning

confidence: 90%

Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

Dheda

Lenders

Magombedze

et al. 2018

Am J Respir Crit Care Med

130

131

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“…MICs were determined (Betts and Wareham, 2014; Singh, 2014; Singh et al, 2017) using the National Committee for Clinical Laboratory Standards (2002) susceptibility testing guidelines in 96-well microtiter plates (SPL Life Sciences, Pocheon, South Korea). Briefly, an overnight culture at a dilution of 1:100 inoculated in TSB was cultured for 24 h in the presence of curcumin (100, 200, or 500 μg/ml) at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Antibiofilm and Antivirulence Efficacies of Flavonoids and Curcumin Against Acinetobacter baumannii

et al. 2019

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Acinetobacter baumannii is well adapted to hospital environments, and the persistence of its chronic infections is mainly due to its ability to form biofilms resistant to conventional antibiotics and host immune systems. Hence, the inhibitions of biofilm formation and virulence characteristics provide other means of addressing infections. In this study, the antibiofilm activities of twelve flavonoids were initially investigated. Three most active flavonoids, namely, fisetin, phloretin, and curcumin, dose-dependently inhibited biofilm formation by a reference A. baumannii strain and by several clinical isolates, including four multidrug-resistant isolates. Furthermore, the antibiofilm activity of curcumin (the most active flavonoid) was greater than that of the well-known biofilm inhibitor gallium nitrate. Curcumin inhibited pellicle formation and the surface motility of A. baumannii . Interestingly, curcumin also showed antibiofilm activity against Candida albicans and mixed cultures of C. albicans and A. baumannii . In silico molecular docking of the biofilm response regulator BfmR showed that the binding efficacy of flavonoids with BfmR was correlated with antibiofilm efficacy. In addition, curcumin treatment diminished A. baumannii virulence in an in vivo Caenorhabditis elegans model without cytotoxicity. The study shows curcumin and other flavonoids have potential for controlling biofilm formation by and the virulence of A. baumannii .

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Determination of Minimum Inhibitory Concentration of Cycloserine in Multidrug Resistant Mycobacterium Tuberculosis Isolates

Cited by 5 publications

References 2 publications

Mechanism-Based Inhibition of the Mycobacterium tuberculosis Branched-Chain Aminotransferase by d- and l-Cycloserine

Mechanism-Based Inhibition of the Mycobacterium tuberculosis Branched-Chain Aminotransferase by d- and l-Cycloserine

Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

Antibiofilm and Antivirulence Efficacies of Flavonoids and Curcumin Against Acinetobacter baumannii

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