scholarly journals New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis

2021 ◽  
Vol 14 (4) ◽  
pp. 361
Author(s):  
Sarentha Chetty ◽  
Tom Armstrong ◽  
Shalu Sharma Kharkwal ◽  
William C. Drewe ◽  
Cristina I. De Matteis ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Protein Crystal ◽  
First Line ◽  
Isoniazid Resistance ◽  
Structure Based Drug Design ◽  
Extensively Drug Resistant ◽  
New Treatment ◽  
Flexible Ligands ◽  
Line Drug

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new ‘direct’ InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expanding on the triclosan structure. Low Minimum Inhibitory Concentrations (MICs) were obtained for benzylphenyl compounds (12, 43 and 44) and di-triclosan derivative (39), against Mycobacterium bovis BCG although these may also be inhibiting other enzymes. The ether linked di-triclosan derivative (38) displayed excellent in vitro isolated enzyme inhibition results comparable with triclosan, but at a higher MIC (125 µg mL−1). These compounds offer good opportunities as leads for further optimisation.

scholarly journals In Vitro Antimycobacterial Activity of Pakistani Beri Honey Using BACTEC MGIT 960

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Abdul Hannan ◽  
Saira Munir ◽  
Muhammad Usman Arshad ◽  
Nabila Bashir
Keyword(s):  
Growth Control ◽  
Antimycobacterial Activity ◽  
Multidrug Resistant ◽  
Bacterial Disease ◽  
First Line ◽  
Development Of Resistance ◽  
Extensively Drug Resistant ◽  
Mdr Tb ◽  
Growth Controls

Background. Tuberculosis (TB) is a chronic bacterial disease. Mycobacterium tuberculosis, being the leading member of the MTB complex, is the main cause of tuberculosis worldwide. Tuberculosis is managed with combination of drugs: streptomycin, isoniazid, rifampicin, ethambutol, and pyrazinamide. Over the recent past years resistance against first line antituberculous drugs has emerged rapidly throughout the world resulting in MDR strains. The new threat in the management of MDR-TB is the development of resistance against second line drugs: aminoglycosides, polypeptides, fluoroquinolones, and thioamides. Multidrug resistant (MDR) and extensively drug resistant TB (XDR) strains have become a major concern to control TB particularly in the developing countries. The need of the hour is to look for new modalities having antimycobacterial activity. Honey has been well known for its antibacterial activity. We intended to explore its antimycobacterial activity against MDR-TB. Objective. The objective of this study was to determine whether Pakistani Beri honey has any antimycobacterial activity. Method. The study was conducted in the Department of Microbiology, University of Health Sciences, Lahore. Clinical isolates (n=21) of MDR-MTB were evaluated for their susceptibility to Beri honey. The isolates were provided, courtesy of Pakistan Medical Research Council. These isolates were identified by MTBc ID test (Becton & Dickinson) and further tested for their antimycobacterial activity using Beri honey. The honey was tested at the following concentrations (v/v): 1%, 2%, 3%, 4%, and 5% in MGIT 960. Growth controls were also inoculated with each isolate (growth control has no concentration of honey, only containing growth of isolate). Results. MDR-TB isolates (n=21) were tested; 3 (14%) isolates were susceptible at 1% v/v honey, while at 2% v/v of honey 18 (86%) isolates were found to be susceptible. All the 21 isolates (n=21) were susceptible at 3% v/v of honey. Conclusion. The present study clearly demonstrates that Pakistani Beri honey possesses significant antimycobacterial activity in vitro. The antimycobacterial activity of Pakistani Beri honey may, therefore, be exploited in an appropriate mouse model.

scholarly journals Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Zhaojing Zong ◽  
Wei Jing ◽  
Jin Shi ◽  
Shu'an Wen ◽  
Tingting Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Novel Mutation ◽  
Multidrug Resistant ◽  
23S Rrna ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Significant Difference ◽  
Mdr Tb

ABSTRACT Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis. In this study, we compared the in vitro activities and MIC distributions of delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC, and rplD genes were analyzed to reveal potential mechanisms underlying the observed oxazolidinone resistance. A total of 240 M. tuberculosis isolates were included in this study, including 120 MDR-TB isolates and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC90 values for M. tuberculosis isolates were 0.25 mg/liter and 0.5 mg/liter, respectively. Based on visual inspection, we tentatively set epidemiological cutoff (ECOFF) values for MIC determinations for linezolid and delpazolid at 1.0 mg/liter and 2.0 mg/liter, respectively. Although no significant difference in resistance rates was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly greater proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR-TB group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, 1 isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC of >16 mg/liter), compared to a delpazolid MIC of 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity was comparable to that of linezolid. A novel mutation within rplD that endowed M. tuberculosis with linezolid, but not delpazolid, resistance was identified.

scholarly journals In Vitro Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Susanne Jacobsson ◽  
Susanne Paukner ◽  
Daniel Golparian ◽  
Jörgen S. Jensen ◽  
Magnus Unemo
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Drug Resistant ◽  
The Novel ◽  
Extensively Drug Resistant ◽  
Optimal Dosing ◽  
And Performance ◽  
Reference Strains

ABSTRACT We evaluated the activity of the novel semisynthetic pleuromutilin lefamulin, inhibiting protein synthesis and growth, and the effect of efflux pump inactivation on clinical gonococcal isolates and reference strains (n = 251), including numerous multidrug-resistant and extensively drug-resistant isolates. Lefamulin showed potent activity against all gonococcal isolates, and no significant cross-resistance to other antimicrobials was identified. Further studies of lefamulin are warranted, including in vitro selection and mechanisms of resistance, pharmacokinetics/pharmacodynamics, optimal dosing, and performance in randomized controlled trials.

scholarly journals Antimicrobial Activity of Ceftazidime-Avibactam Tested against Multidrug-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Isolates from U.S. Medical Centers, 2013 to 2016

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Dee Shortridge ◽  
Rodrigo E. Mendes ◽  
Robert K. Flamm
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Large Collection ◽  
Content Type ◽  
Negative Results ◽  
Medical Centers ◽  
Extensively Drug Resistant ◽  
Genes Encoding

ABSTRACT The in vitro activity of ceftazidime-avibactam and many comparator agents was determined against various resistant subsets of organisms selected among 36,380 Enterobacteriaceae and 7,868 Pseudomonas aeruginosa isolates. The isolates were consecutively collected from 94 U.S. hospitals, and all isolates were tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories). Enterobacteriaceae isolates resistant to carbapenems (CRE) and/or ceftazidime-avibactam (MIC ≥ 16 μg/ml) were evaluated for the presence of genes encoding extended-spectrum β-lactamases and carbapenemases. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 μg/ml and was active against multidrug-resistant (MDR; n = 2,953; MIC50/90, 0.25/1 μg/ml; 99.2% susceptible), extensively drug-resistant (XDR; n = 448; MIC50/90, 0.5/2 μg/ml; 97.8% susceptible), and CRE (n = 513; MIC50/90, 0.5/2 μg/ml; 97.5% susceptible) isolates. Only 82.2% of MDR Enterobacteriaceae (n = 2,953) and 64.2% of ceftriaxone-nonsusceptible Klebsiella pneumoniae (n = 1,063) isolates were meropenem susceptible. Among Enterobacter cloacae (22.2% ceftazidime nonsusceptible), 99.8% of the isolates, including 99.3% of the ceftazidime-nonsusceptible isolates, were ceftazidime-avibactam susceptible. Only 23 of 36,380 Enterobacteriaceae (0.06%) isolates were ceftazidime-avibactam nonsusceptible, including 9 metallo-β-lactamase producers and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all β-lactamases tested. Ceftazidime-avibactam showed potent activity against P. aeruginosa (MIC50/90, 2/4 μg/ml; 97.1% susceptible), including MDR (MIC50/90, 4/16 μg/ml; 86.5% susceptible) isolates, and inhibited 71.8% of isolates nonsusceptible to meropenem, piperacillin-tazobactam, and ceftazidime (n = 628). In summary, ceftazidime-avibactam demonstrated potent activity against a large collection (n = 44,248) of contemporary Gram-negative bacilli isolated from U.S. patients, including organisms resistant to most currently available agents, such as CRE and meropenem-nonsusceptible P. aeruginosa.

scholarly journals In Vitro Activity of Lefamulin against Sexually Transmitted Bacterial Pathogens

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Susanne Paukner ◽  
Astrid Gruss ◽  
Jørgen Skov Jensen
Keyword(s):  
Chlamydia Trachomatis ◽  
Bacterial Pathogens ◽  
Mycoplasma Genitalium ◽  
Standard Of Care ◽  
Multidrug Resistant ◽  
In Vitro Activity ◽  
First Line ◽  
Content Type ◽  
Sexually Transmitted

ABSTRACT The pleuromutilin antibiotic lefamulin demonstrated in vitro activity against the most relevant bacterial pathogens causing sexually transmitted infections (STI), including Chlamydia trachomatis (MIC 50/90 , 0.02/0.04 mg/liter; n = 15), susceptible and multidrug-resistant Mycoplasma genitalium (MIC range, 0.002 to 0.063 mg/liter; n = 6), and susceptible and resistant Neisseria gonorrhoeae (MIC 50/90 , 0.12/0.5 mg/liter; n = 25). The results suggest that lefamulin could be a promising first-line antibiotic for the treatment of STI, particularly in populations with high rates of resistance to standard-of-care antibiotics.

scholarly journals Multicenter evaluation of TB-SPRINT 59-Plex Beamedex®: accuracy and cost analysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Regina Bones Barcellos ◽  
Isabela Neves de Almeida ◽  
Elisangela Costa da Silva ◽  
Harrison Magdinier Gomes ◽  
Lida Jouca de Assis Figueredo ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Cost Evaluation ◽  
Laboratory Research ◽  
Activity Based Costing ◽  
In Vitro Diagnostics ◽  
Isoniazid Resistance ◽  
Molecular Tests ◽  
Mdr Tb ◽  
Mean Cost

Abstract Background Molecular tests can allow the rapid detection of tuberculosis (TB) and multidrug-resistant TB (MDR-TB). TB-SPRINT 59-Plex Beamedex® is a microbead-based assay developed for the simultaneous spoligotyping and detection of MDR-TB. The accuracy and cost evaluation of new assays and technologies are of great importance for their routine use in clinics and in research laboratories. The aim of this study was to evaluate the performance of TB-SPRINT at three laboratory research centers in Brazil and calculate its mean cost (MC) and activity-based costing (ABC). Methods TB-SPRINT data were compared with the phenotypic and genotypic profiles obtained using Bactec™ MGIT™ 960 system and Genotype® MTBDRplus, respectively. Results Compared with MGIT, the accuracies of TB-SPRINT for the detection of rifampicin and isoniazid resistance ranged from 81 to 92% and 91.3 to 93.9%, respectively. Compared with MTBDRplus, the accuracies of TB-SPRINT for rifampicin and isoniazid were 99 and 94.2%, respectively. Moreover, the MC and ABC of TB-SPRINT were USD 127.78 and USD 109.94, respectively. Conclusion TB-SPRINT showed good results for isoniazid and rifampicin resistance detection, but still needs improvement to achieve In Vitro Diagnostics standards.

In Vitro Activity of Imipenem/Relebactam and Ceftolozane/Tazobactam Against Clinical Isolates of Gram-negative Bacilli With Difficult-to-Treat Resistance and Multidrug-resistant Phenotypes—Study for Monitoring Antimicrobial Resistance Trends, United States 2015–2017

2020 ◽  
Author(s):  
James A Karlowsky ◽  
Sibylle H Lob ◽  
Janet Raddatz ◽  
Daryl D DePestel ◽  
Katherine Young ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
First Line ◽  
Clin Microbiol Infect ◽  
Gram Negative ◽  
Novel Approach ◽  
The Us ◽  
Urinary Isolates

Abstract Background Multidrug-resistant (MDR) bacteria are frequently defined using the criteria established by Magiorakos et al [Clin Microbiol Infect 2012;18:268–81]. Difficult-to-treat resistance (DTR) [Kadri et al, Clin Infect Dis 2018;67:1803–14] is a novel approach to defining resistance in gram-negative bacilli focusing on treatment-limiting resistance to first-line agents (all β-lactams and fluoroquinolones). Methods Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MICs) were determined for imipenem/relebactam, ceftolozane/tazobactam, and comparators against respiratory, intraabdominal, and urinary isolates of Enterobacterales (n = 10 516) and Pseudomonas aeruginosa (n = 2732) collected in 26 US hospitals in 2015–2017. Results Among all Enterobacterales, 1.0% of isolates were DTR and 15.6% were MDR; 8.4% of P. aeruginosa isolates were DTR and 32.4% were MDR. MDR rates for Enterobacterales and DTR and MDR rates for P. aeruginosa were significantly higher (P < .05) in isolates collected in intensive care units (ICUs) than in non-ICUs and in respiratory tract isolates than in intraabdominal or urinary tract isolates. In addition, 82.4% of DTR and 92.1% of MDR Enterobacterales and 62.2% of DTR and 82.2% of MDR P. aeruginosa were imipenem/relebactam-susceptible, and 1.5% of DTR and 65.8% of MDR Enterobacterales and 67.5% of DTR and 84.0% of MDR P. aeruginosa were ceftolozane/tazobactam-susceptible. Conclusions MDR phenotypes defined using the Magiorakos criteria may overcall treatment-limiting resistance in gram-negative bacilli. In the US, DTR Enterobacterales were infrequent, while MDR Enterobacterales isolates and DTR and MDR P. aeruginosa were common. Imipenem/relebactam (Enterobacterales, P. aeruginosa) and ceftolozane/tazobactam (P. aeruginosa) retained in vitro activity against most DTR and MDR isolates.

scholarly journals 7-Chloroquinolin-4-yl Arylhydrazone Derivatives: Synthesis and Antifungal Activity

2011 ◽  
Vol 11 ◽  
pp. 1489-1495 ◽  
Author(s):  
Auri R. Duval ◽  
Pedro H. Carvalho ◽  
Maieli C. Soares ◽  
Daniela P. Gouvêa ◽  
Geonir M. Siqueira ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Rational Design ◽  
Antifungal Agents ◽  
Inhibitory Concentration ◽  
First Line ◽  
Minimum Fungicidal Concentration ◽  
Starting Point ◽  
Line Drug ◽  
In Vitro Antifungal Activity

Fifteen 7-chloro-4-arylhydrazonequinolines have been evaluated for their in vitro antifungal activity against eight oral fungi:Candida albicans, C. parapsilosis, C. lipolytica, C. tropicalis, C. famata, C. glabrata, Rhodutorula mucilaginosa, andR. glutinis. Several compounds exhibited minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) activities comparable with the first-line drug fluconazole. These results could be considered as an important starting point for the rational design of new antifungal agents.

scholarly journals In Vitro Monitoring of Plasmodium falciparum Drug Resistance in French Guiana: a Synopsis of Continuous Assessment from 1994 to 2005

2007 ◽  
Vol 52 (1) ◽  
pp. 288-298 ◽  
Author(s):  
Eric Legrand ◽  
Béatrice Volney ◽  
Jean-Baptiste Meynard ◽  
Odile Mercereau-Puijalon ◽  
Philippe Esterre
Keyword(s):  
Plasmodium Falciparum ◽  
French Guiana ◽  
Control Program ◽  
Drug Susceptibility ◽  
Warning Signs ◽  
Strongly Correlated ◽  
First Line ◽  
Drug Pressure ◽  
Line Drug

ABSTRACT Implemented as one arm of the malaria control program in French Guiana in the early 1990s, our laboratory has since established in vitro profiles for parasite drug susceptibility to a panel of eight antimalarials for more than 1,000 Plasmodium falciparum isolates from infected patients. The quinine-doxycycline combination was introduced in 1995 as the first-line drug treatment against uncomplicated P. falciparum malaria, replacing chloroquine, and the first-line drug combination was changed to the artemether-lumefantrine combination in 2002. Resistance to chloroquine declined 5 years after it was dropped in 1995 as the first-line drug, but unlike similar situations in Africa, there was a rapid halt to this decline. Doxycycline susceptibility substantially decreased from 2002 to 2005, suggesting parasite selection under quinine-doxycycline drug pressure. Susceptibility to mefloquine decreased from 1997 onward. Throughout the period from 1994 to 2005, most isolates were sensitive in vitro to quinine, amodiaquine, and atovaquone. Susceptibility to amodiaquine was strongly correlated with that to chloroquine and to a lesser extent with that to mefloquine and halofantrine. Susceptibilities to mefloquine and to halofantrine were also strongly correlated. There were two alerts issued for in vitro artemether resistance in the period from 2002 to 2003 and again in 2005, both of which could be associated with the presence of an S769N polymorphism in the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-type P. falciparum ATPase6 (PfATPase6) gene. Analysis of susceptibility to lumefantrine, conducted for the first time in 2005, indicates an alarming rate of elevated 50% inhibitory concentrations. In vitro monitoring of parasite drug susceptibility should be pursued to further document the consequences of specific drug policies on the local parasite population and, in particular, to establish profiles of susceptibility to individual components of drug combinations to provide early warning signs of emerging parasite resistance.

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