Anti-Mycobacterium tuberculosis activity of antituberculosis drugs and amoxicillin/clavulanate combination

Pagliotto, Aline Daniele Furlan; Caleffi-Ferracioli, Katiany Rizzieri; Lopes, Mariana Aparecida; Baldin, Vanessa Pietrowski; Leite, Clarice Queico Fujimura; Pavan, Fernando Rogério; Scodro, Regiane Bertin de Lima; Siqueira, Vera Lúcia Dias; Cardoso, Rosilene Fressatti

doi:10.1016/j.jmii.2015.08.025

Cited by 28 publications

(11 citation statements)

References 10 publications

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“…The in vitro growth interaction of bacteria with the inhibitors and the first line drugs such as rifampicin (RIF)/INH was determined by resazurin drugs combination microtiter assay [ 33 ]. Two-fold serial dilutions ranging from 12.5 mg/L to 0.04 mg/L for RIF/INH were combined with the same concentration of inhibitor (ranging from 12.5 mg/L to 0.04 mg/L) in wells of microtiter plates followed by the addition of bacteria and resazurin solution as described above.…”

Section: Methodsmentioning

confidence: 99%

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Rational design of drug-like compounds targeting Mycobacterium marinum MelF protein

et al. 2017

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The mycobacterial mel2 locus (mycobacterial enhanced infection locus, Rv1936-1941) is Mycobacterium marinum and M. tuberculosis specific, which can withstand reactive oxygen species (ROS) and reactive nitrogen species (RNS) induced stress. A library of over a million compounds was screened using in silico virtual ligand screening (VLS) to identify inhibitors against the modeled structure of MelF protein expressed by melF of mel2 locus so that M. marinum’s ability to withstand ROS/RNS stress could be reduced. The top ranked 1000 compounds were further screened to identify 178 compounds to maximize the scaffold diversity by manually evaluating the interaction of each compound with the target site. M. marinum melF was cloned, expressed and purified as maltose binding protein (MBP)-tagged recombinant protein in Escherichia coli. After establishing the flavin dependent oxidoreductase activity of MelF (~ 84 kDa), the inhibitors were screened for the inhibition of enzyme activity of whole cell lysate (WCL) and the purified MelF. Amongst these, 16 compounds could significantly inhibit the enzyme activity of purified MelF. For the six best inhibitory compounds, the minimal inhibitory concentration (MIC) was determined to be 3.4–19.4 μM and 13.5–38.8 μM for M. marinum and M. tuberculosis, respectively. Similarly, the minimal bactericidal concentration (MBC) was determined to be 6.8–38.8 μM and 27–38.8 μM against M. marinum and M. tuberculosis, respectively. One compound each in combination with isoniazid (INH) also showed synergistic inhibitory effect against M. marinum and M. tuberculosis with no cytotoxicity in HeLa cells. Interestingly, these inhibitors did not display any non-specific protein-structure destabilizing effect. Such inhibitors targeting the anti-ROS/RNS machinery may facilitate the efficient killing of replicating and nonreplicating mycobacteria inside the host cells.

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Section: Methodsmentioning

confidence: 99%

“…The effects of the drug combinations were classified as synergistic (FICI ≤ 0.5), additive or no interaction (FICI > 0.5–4), and antagonistic (FICI > 4) as described by Pagliotto et al [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

Rational design of drug-like compounds targeting Mycobacterium marinum MelF protein

et al. 2017

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“…Furthermore, the ␤-lactamase inhibitor clavulanate as a component of triple combinations including cephalosporins (and other beta-lactams) proved to be a key synergistic partner due to its ability to rescue the activity of RIF against a RIF-resistant strain (2). A combination of amoxicillin-clavulanate with first-line anti-TB drugs has also been explored and showed potent synergism against MDR isolates (4). Repurposing of drugs such as spectinomycin was also studied to test the concept that clinically available antibiotics with limited efficacy against M. tuberculosis might be used for TB treatment when coadministered with macrolides and azoles (5).…”

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confidence: 99%

Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169)

Lupien

Vocat

Foo

et al. 2018

Antimicrob Agents Chemother

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The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Intensive efforts have been made to develop new antibiotics or to repurpose old drugs, and several of these are currently being evaluated in clinical trials for their antitubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone PBTZ169, which is currently being evaluated in phase I/II clinical trials. Here, we determined the and activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD), or sutezolid (STZ) reduced the bacterial burden by 2 logs compared to that achieved with the drugs alone, indicating synergism. MCZ also displayed synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity was found for most combinations, suggesting that MCZ could be added to different TB treatment regimens without any significant adverse effects.

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“…Beta-lactams are reported to have early antitubercular activity comparable to the conventional ATT drugs other than isoniazid. 17 We hypothesize these reasons for Xpert positive culture negative results.…”

Section: Discussionmentioning

confidence: 98%

Diagnostic Utility of Bronchoalveolar Lavage Xpert MTB/RIF Assay in Suspected Cases of Pulmonary Tuberculosis

Bashir¹,

Nahvi²,

Khan³

et al. 2019

IJCMR

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Introduction: Limited data on the diagnostic accuracy of the Xpert MTB/RIF assay using bronchoalveolar lavage fluid from patients with suspected pulmonary tuberculosis have been reported in India. The aim of this study was to evaluate Xpert MTB/RIF on bronchoalveolar lavage fluid in suspected PTB patients by comparing with AFB smear microscopy and culture Material and methods: A cross sectional observational study was carried on a total of 450 bronchoalveolar lavage fluid were processed by Xpert MTB/RIF between January 2018 and December 2018. Culture results were considered as the gold standard for diagnosis of TB. Sensitivity, specificity, PPV, and negative predictive value (NPV) for the diagnosis of active PTB were calculated using the website http://vassarstats. net/clin1.html. SPSS statistics version 17.0 software (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. Results: Xpert MTB/RIF had a sensitivity of 97.05% (95% CI 88.8-99.4) while the specificity of 90.05% (95% CI 86.4-92.7) in culture confirmed cases and those for smear microscopy was 36.7% (95% CI 25.6-49.3) and 100% (95% CI 98.7-100) respectively. Conclusion: The Xpert MTB/RIF assay is a rapid and simple technique with significantly higher sensitivity for diagnosing pulmonary TB compared to smear microscopy.(p < 0.005

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Anti-Mycobacterium tuberculosis activity of antituberculosis drugs and amoxicillin/clavulanate combination

Cited by 28 publications

References 10 publications

Rational design of drug-like compounds targeting Mycobacterium marinum MelF protein

Rational design of drug-like compounds targeting Mycobacterium marinum MelF protein

Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169)

Diagnostic Utility of Bronchoalveolar Lavage Xpert MTB/RIF Assay in Suspected Cases of Pulmonary Tuberculosis

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