scholarly journals Genomic Analysis of the Evolution of Fluoroquinolone Resistance in Mycobacterium tuberculosis Prior to Tuberculosis Diagnosis

2016 ◽  
Vol 60 (11) ◽  
pp. 6600-6608 ◽  
Author(s):  
Danfeng Zhang ◽  
James E. Gomez ◽  
Jung-Yien Chien ◽  
Nathan Haseley ◽  
Christopher A. Desjardins ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
De Novo ◽  
Genomic Analysis ◽  
Fluoroquinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
History Of ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data

ABSTRACTFluoroquinolones (FQs) are effective second-line drugs for treating antibiotic-resistant tuberculosis (TB) and are being considered for use as first-line agents. Because FQs are used to treat a range of infections, in a setting of undiagnosed TB, there is potential to select for drug-resistantMycobacterium tuberculosismutants during FQ-based treatment of other infections, including pneumonia. Here we present a detailed characterization of ofloxacin-resistantM. tuberculosissamples isolated directly from patients in Taiwan, which demonstrates that selection for FQ resistance can occur within patients who have not received FQs for the treatment of TB. Several of these samples showed no mutations ingyrAorgyrBbased on PCR-based molecular assays, but genome-wide next-generation sequencing (NGS) revealed minority populations ofgyrAand/orgyrBmutants. In other samples with PCR-detectablegyrAmutations, NGS revealed subpopulations containing alternative resistance-associated genotypes. Isolation of individual clones from these apparently heterogeneous samples confirmed the presence of the minority drug-resistant variants suggested by the NGS data. Further NGS of these purified clones established evolutionary links between FQ-sensitive and -resistant clones derived from the same patient, suggestingde novoemergence of FQ-resistant TB. Importantly, most of these samples were isolated from patients without a history of FQ treatment for TB. Thus, selective pressure applied by FQ monotherapy in the setting of undiagnosed TB infection appears to be able to drive the full or partial emergence of FQ-resistantM. tuberculosis, which has the potential to confound diagnostic tests for antibiotic susceptibility and limit the effectiveness of FQs in TB treatment.

scholarly journals Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Qi Ouyang ◽  
Kehong Zhang ◽  
Dachuan Lin ◽  
Carl G. Feng ◽  
Yi Cai ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
New Host ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Receptor Modulator ◽  
Resistant Tuberculosis ◽  
Negative Side Effects

ABSTRACT Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection. There is a clear need for new treatment strategy against TB. It has been reported that tamoxifen, known as a selective estrogen receptor modulator (SERM), exhibits antimycobacterial activity and inhibits M. tuberculosis growth in macrophages. However, it remains unknown whether such antimicrobial activity is a general property of all SERMs and how it works. In this study, we identified that bazedoxifene (BZA), a newer SERM, inhibits intracellular M. tuberculosis growth in macrophages. BZA treatment increases autophagosome formation and LC3B-II protein expression in M. tuberculosis-infected macrophages. We further demonstrated that the enhancement of autophagy by BZA is dependent on increased reactive oxygen species (ROS) production and associated with phosphorylation of Akt/mTOR signaling. In summary, our data reveal a previously unappreciated antimicrobial function of BZA and suggest that future investigation focusing on the mechanism of action of SERMs in macrophages may lead to new host-directed therapies against TB. IMPORTANCE Since current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-directed therapy (HDT) has become a promising idea to modulate host cell responses to enhance protective immunity against pathogens. Bazedoxifene (BZA), which belongs to a new generation of SERMs, shows the ability to inhibit the growth of M. tuberculosis in macrophages and is associated with autophagy. Our findings reveal a previously unrecognized antibacterial function of BZA. We propose that the mechanism of SERMs action in macrophages may provide a new potential measure for host-directed therapies against TB.

scholarly journals Whole-Genome Sequencing of Mycobacterium tuberculosis Provides Insight into the Evolution and Genetic Composition of Drug-Resistant Tuberculosis in Belarus

2016 ◽  
Vol 55 (2) ◽  
pp. 457-469 ◽  
Author(s):  
Kurt R. Wollenberg ◽  
Christopher A. Desjardins ◽  
Aksana Zalutskaya ◽  
Vervara Slodovnikova ◽  
Andrew J. Oler ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
De Novo ◽  
Acquired Resistance ◽  
Multiple Infections ◽  
Drug Resistant ◽  
Genetic Composition ◽  
Hiv Patients ◽  
Treatment Protocols ◽  
Content Type ◽  
Phenotypic Resistance

ABSTRACTThe emergence and spread of drug-resistantMycobacterium tuberculosis(DR-TB) are critical global health issues. Eastern Europe has some of the highest incidences of DR-TB, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. To better understand the genetic composition and evolution of MDR- and XDR-TB in the region, we sequenced and analyzed the genomes of 138M. tuberculosisisolates from 97 patients sampled between 2010 and 2013 in Minsk, Belarus. MDR and XDR-TB isolates were significantly more likely to belong to the Beijing lineage than to the Euro-American lineage, and known resistance-conferring loci accounted for the majority of phenotypic resistance to first- and second-line drugs in MDR and XDR-TB. Using a phylogenomic approach, we estimated that the majority of MDR-TB was due to the recent transmission of already-resistantM. tuberculosisstrains rather than repeatedde novoevolution of resistance within patients, while XDR-TB was acquired through both routes. Longitudinal sampling ofM. tuberculosisfrom 34 patients with treatment failure showed that most strains persisted genetically unchanged during treatment or acquired resistance to fluoroquinolones. HIV+ patients were significantly more likely to have multiple infections over time than HIV− patients, highlighting a specific need for careful infection control in these patients. These data provide a better understanding of the genomic composition, transmission, and evolution of MDR- and XDR-TB in Belarus and will enable improved diagnostics, treatment protocols, and prognostic decision-making.

scholarly journals Susceptibility Testing of Extensively Drug-Resistant and Pre-Extensively Drug-Resistant Mycobacterium tuberculosis against Levofloxacin, Linezolid, and Amoxicillin-Clavulanate

2013 ◽  
Vol 57 (6) ◽  
pp. 2522-2525 ◽  
Author(s):  
Imran Ahmed ◽  
Kauser Jabeen ◽  
Raunaq Inayat ◽  
Rumina Hasan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Susceptibility Testing ◽  
Critical Concentration ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Fluoroquinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Amoxicillin Clavulanate

ABSTRACTPakistan is a high-burden country for tuberculosis (TB). The emergence and increasing incidence of extensively drug-resistant (XDR) TB has been reported in Pakistan. Similarly, the prevalence of multidrug-resistant TB infections with fluoroquinolone resistance (pre-XDR) is also increasing. To treat these infections, local drug susceptibility patterns of alternate antituberculosis agents, including levofloxacin (LVX), linezolid (LZD), and amoxicillin-clavulanate (AMC), is urgently needed. The aim of this study was to determine the susceptibility frequencies of drug-resistant (DR)Mycobacterium tuberculosisagainst LVX, LZD, and AMC. All susceptibilities were determined on Middlebrook 7H10 agar. A critical concentration was used for LVX (1 μg/ml), whereas MICs were determined for LZD and AMC.M. tuberculosisH37Rv was used as a control strain. A total of 102M. tuberculosisisolates (XDR,n= 59; pre-XDR,n= 43) were tested. Resistance to LVX was observed in 91.2% (93/102). Using an MIC value of 0.5 μg/ml as a cutoff, resistance to LZD (MIC ≥ 1 μg/ml) was noted in 5.9% (6/102). Although the sensitivity breakpoints are not established for AMC, the MIC values were high (>16 μg/ml) in 97.1% (99/102). Our results demonstrate that LZD may be effective for the treatment of XDR and pre-XDR cases from Pakistan. High resistance rates against LVX in our study suggest the use of this drug with caution for DR-TB cases from this area. Drug susceptibility testing against LVX and AMC may be helpful in complicated and difficult-to-manage cases.

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 Mutation in an Unannotated Protein Confers Carbapenem Resistance in Mycobacterium tuberculosis

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Pankaj Kumar ◽  
Amit Kaushik ◽  
Drew T. Bell ◽  
Varsha Chauhan ◽  
Fangfang Xia ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Genetic Basis ◽  
Carbapenem Resistance ◽  
Drug Resistant ◽  
Binding Affinities ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Recent Developments

ABSTRACT β-Lactams are the most widely used antibacterials. Among β-lactams, carbapenems are considered the last line of defense against recalcitrant infections. As recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before Mycobacterium tuberculosis strains resistant to these drugs will emerge. In the present study, we investigated the genetic basis that confers such resistance. To our surprise, instead of mutations in the known β-lactam targets, a single nucleotide polymorphism in the Rv2421c-Rv2422 intergenic region was common among M. tuberculosis mutants selected with meropenem or biapenem. We present data supporting the hypothesis that this locus harbors a previously unidentified gene that encodes a protein. This protein binds to β-lactams, slowly hydrolyzes the chromogenic β-lactam nitrocefin, and is inhibited by select penicillins and carbapenems and the β-lactamase inhibitor clavulanate. The mutation results in a W62R substitution that reduces the protein's nitrocefin-hydrolyzing activity and binding affinities for carbapenems.

scholarly journals Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Adebisi Ajileye ◽  
Nataly Alvarez ◽  
Matthias Merker ◽  
Timothy M. Walker ◽  
Suriya Akter ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Specific Resistance ◽  
Multidrug Resistant ◽  
Fluoroquinolone Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Content Type ◽  
Synonymous Mutations ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

ABSTRACT In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.

scholarly journals Meropenem-Clavulanic Acid Has HighIn VitroActivity against Multidrug-Resistant Mycobacterium tuberculosis

2015 ◽  
Vol 59 (6) ◽  
pp. 3630-3632 ◽  
Author(s):  
L. Davies Forsman ◽  
C. G. Giske ◽  
J. Bruchfeld ◽  
T. Schön ◽  
P. Juréen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clavulanic Acid ◽  
Treatment Option ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Potential Treatment ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

ABSTRACTWe investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68Mycobacterium tuberculosisisolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.

scholarly journals Sequence Analysis of Fluoroquinolone Resistance-Associated GenesgyrAandgyrBin Clinical Mycobacterium tuberculosis Isolates from Patients Suspected of Having Multidrug-Resistant Tuberculosis in New Delhi, India

2016 ◽  
Vol 54 (9) ◽  
pp. 2298-2305 ◽  
Author(s):  
Ritu Singhal ◽  
Paul R. Reynolds ◽  
Jamie L. Marola ◽  
L. Elaine Epperson ◽  
Jyoti Arora ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Indian Subcontinent ◽  
Amino Acid Position ◽  
Multidrug Resistant ◽  
High Rate ◽  
Fluoroquinolone Resistance ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Fluoroquinolones (FQs) are broad-spectrum antibiotics recommended for the treatment of multidrug-resistant tuberculosis (MDR-TB) patients. FQ resistance, caused by mutations in thegyrAandgyrBgenes ofMycobacterium tuberculosis, is increasingly reported worldwide; however, information on mutations occurring in strains from the Indian subcontinent is scarce. Hence, in this study, we aimed to characterize mutations in thegyrAandgyrBgenes of acid-fast bacillus (AFB) smear-positive sediments or ofM. tuberculosisisolates from AFB smear-negative samples from patients in India suspected of having MDR-TB. A total of 152 samples from patients suspected of having MDR-TB were included in the study. One hundred forty-six strains detected in these samples were characterized by sequencing of thegyrAandgyrBgenes. The extracted DNA was subjected to successive amplifications using a nested PCR protocol, followed by sequencing. A total of 27 mutations were observed in thegyrAgenes of 25 strains, while no mutations were observed in thegyrBgenes. The most common mutations occurred at amino acid position 94 (13/27 [48.1%]); of these, the D94G mutation was the most prevalent. ThegyrAmutations were significantly associated with patients with rifampin (RIF)-resistant TB. Heterozygosity was seen in 4/27 (14.8%) mutations, suggesting the occurrence of mixed populations with different antimicrobial susceptibilities. A high rate of FQ-resistant mutations (17.1%) was obtained among the isolates of TB patients suspected of having MDR-TB. These observations emphasize the need for accurate and rapid molecular tests for the detection of FQ-resistant mutations at the time of MDR-TB diagnosis.

scholarly journals Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

2018 ◽  
Vol 63 (2) ◽  
pp. e01489-18 ◽  
Author(s):  
Sander P. van Rijn ◽  
Marlanka A. Zuur ◽  
Richard Anthony ◽  
Bob Wilffert ◽  
Richard van Altena ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
International Travel ◽  
Future Research ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Susceptibility Tests

ABSTRACT Multi- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis. To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo, and clinical data on carbapenems in the treatment of M. tuberculosis and to detect knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall, the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and laboratory strains of M. tuberculosis, are consistent. In vitro, the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore, it is impossible in practice to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, including one prospective, two observational, and seven retrospective clinical studies to assess the effectiveness, safety, and tolerability of three different carbapenems (imipenem, meropenem, and ertapenem). We found no clear evidence at the present time to select one particular carbapenem among the different candidate compounds to design an effective M/XDR-TB regimen. Therefore, more clinical evidence and dose optimization substantiated by hollow-fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

scholarly journals Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable β-Lactam Antibiotic

2014 ◽  
Vol 59 (2) ◽  
pp. 1308-1319 ◽  
Author(s):  
Neeraj Dhar ◽  
Vincent Dubée ◽  
Lluis Ballell ◽  
Guillaume Cuinet ◽  
Jean-Emmanuel Hugonnet ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Single Cells ◽  
Alternative Therapy ◽  
Potential Candidate ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Lactam Antibiotic ◽  
Orally Bioavailable

ABSTRACTRecent clinical studies indicate that meropenem, a β-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a β-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable β-lactam, efficiently killsMycobacterium tuberculosiseven in the absence of clavulanate. The target enzymes,l,d-transpeptidases, were inactivated 6- to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.

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