scholarly journals Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility.

1996 ◽  
Vol 40 (1) ◽  
pp. 14-16 ◽  
Author(s):  
S P Klemens ◽  
C A Sharpe ◽  
M H Cynamon
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Efficacy ◽  
Viable Cell ◽  
Test System ◽  
Infection Model ◽  
Drug Resistant ◽  
In Vitro Susceptibility ◽  
Cell Counts ◽  
Treatment Of Infection

The activity of pyrazinamide (PZA) against eight isolates of Mycobacterium tuberculosis in a murine infection model was evaluated. M. tuberculosis isolates with various degrees of in vitro susceptibility to PZA (MIC range, 32 to > 2,048 micrograms/ml) were used. Four-week-old female mice were infected intravenously with approximately 10(7) viable M. tuberculosis organisms. PZA at 150 mg/kg of body weight was started 1 day postinfection and given 5 days/week for 4 weeks. Infected but untreated mice were compared with PZA-treated mice. Mice were sacrificed at the completion of the treatment period, and viable cell counts were determined from homogenates of spleens and right lungs. PZA had activity in the murine test system against M. tuberculosis isolates for which the MICs were < or = 256 micrograms/ml. However, there was an inconsistent correlation between the absolute MICs and the reductions in organ viable cell counts. Studies with drug-resistant M. tuberculosis isolates with an isogenic background would improve evaluation of drug efficacy in the murine test system. Further evaluation of antimycobacterial agents against monodrug-resistant isolates will provide data that will be useful for development of algorithms for treatment of infection with drug-resistant organisms.

scholarly journals Activities of Several Novel Oxazolidinones againstMycobacterium tuberculosis in a Murine Model

1999 ◽  
Vol 43 (5) ◽  
pp. 1189-1191 ◽  
Author(s):  
M. H. Cynamon ◽  
S. P. Klemens ◽  
C. A. Sharpe ◽  
S. Chase
Keyword(s):  
Body Weight ◽  
Mycobacterium Tuberculosis ◽  
Dose Response ◽  
Murine Model ◽  
Clinical Studies ◽  
Viable Cell ◽  
Test System ◽  
Cell Counts ◽  
Dose Response Study

ABSTRACT The activities of linezolid, eperezolid, and PNU-100480 were evaluated in a murine model of tuberculosis. Approximately 107 viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old outbred CD-1 mice. In the first study, treatment was started 1 day postinfection and was given by gavage for 4 weeks. Viable cell counts were determined from homogenates of spleens and lungs. PNU-100480 was as active as isoniazid. Linezolid was somewhat less active than PNU-100480 and isoniazid. Eperezolid had little activity in this model. In the next two studies, treatment was started 1 week postinfection. A dose-response study was performed with PNU-100480 and linezolid (both at 25, 50, and 100 mg/kg of body weight). PNU-100480 was more active than linezolid, and its efficacy increased with an escalation of the dose. Subsequently, the activity of PNU-100480 alone and in combination with rifampin or isoniazid was evaluated and was compared to that of isoniazid-rifampin. The activity of PNU-100480 was similar to that of isoniazid and/or rifampin in the various combinations tested. Further evaluation of these oxazolidinones in the murine test system would be useful prior to the development of clinical studies with humans.

scholarly journals In Vitro Susceptibility of Mycobacterium tuberculosis Clinical Isolates to Garenoxacin and DA-7867

2005 ◽  
Vol 49 (10) ◽  
pp. 4351-4353 ◽  
Author(s):  
Lucio Vera-Cabrera ◽  
Jorge Castro-Garza ◽  
Adrian Rendon ◽  
Jorge Ocampo-Candiani ◽  
Oliverio Welsh ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Active Drug ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
In Vitro Susceptibility

ABSTRACT The in vitro activities of DA-7867, a novel oxazolidinone, and garenoxacin (BMS-284756) were compared to those of linezolid in 67 susceptible and drug-resistant clinical isolates of Mycobacterium tuberculosis. DA-7867 was the most active drug with an MIC90 of 0.125 μg/ml, compared to the MIC90s of 4 μg/ml of garenoxacin and 2 μg/ml of linezolid.

scholarly journals 1250. Novel Boronic Acid Transition State Analogs (BATSI) with in vitro inhibitory activity against class A, B and C β-lactamases

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S643-S643
Author(s):  
Maria F Mojica ◽  
Christopher Bethel ◽  
Emilia Caselli ◽  
Magdalena A Taracila ◽  
Fabio Prati ◽  
...  
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Covalent Bond ◽  
Thiol Group ◽  
Viable Cell ◽  
Free Thiol ◽  
Transition State Analogs ◽  
Cell Counts ◽  
Free Thiol Group

Abstract Background Catalytic mechanisms of serine β-lactamases (SBL; classes A, C and D) and metallo-β-lactamases (MBLs) have directed divergent strategies towards inhibitor design. SBL inhibitors act as high affinity substrates that -as in BATSIs- form a reversible, dative covalent bond with the conserved active site Ser. MBL inhibitors bind the active-site Zn2+ ions and displace the nucleophilic OH-. Herein, we explore the efficacy of a series of BATSI compounds with a free-thiol group at inhibiting both SBL and MBL. Methods Exploratory compounds were synthesized using stereoselective homologation of (+) pinandiol boronates to introduce the amino group on the boron-bearing carbon atom, which was subsequently acylated with mercaptopropanoic acid. Representative SBL (KPC-2, ADC-7, PDC-3 and OXA-23) and MBL (IMP-1, NDM-1 and VIM-2) were purified and used for the kinetic characterization of the BATSIs. In vitro activity was evaluated by a modified time-kill curve assay, using SBL and MBL-producing strains. Results Kinetic assays revealed that IC50 values ranged from 1.3 µM to &gt;100 µM for this series. The best compound, s08033, demonstrated inhibitory activity against KPC-2, VIM-2, ADC-7 and PDC-3, with IC50 in the low μM range. Reduction of at least 1.5 log10-fold of viable cell counts upon exposure to sub-lethal concentrations of antibiotics (AB) + s08033, compared to the cells exposed to AB alone, demonstrated the microbiological activity of this novel compound against SBL- and MBL-producing E. coli (Table 1). Table 1 Conclusion Addition of a free-thiol group to the BATSI scaffold increases the range of these compounds resulting in a broad-spectrum inhibitor toward clinically important carbapenemases and cephalosporinases. Disclosures Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)

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.

In Vitro Anti-Biofilm Activity of Hydrogen-Peroxide Generating Electrochemical Bandage Against Yeast Biofilms

2021 ◽  
Author(s):  
Yash S. Raval ◽  
Abdelrhman Mohamed ◽  
Jayawant N. Mandrekar ◽  
Cody Fisher ◽  
Kerryl E. Greenwood-Quaintance ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Microscopic Analysis ◽  
Viable Cell ◽  
Wound Infections ◽  
Unique Challenge ◽  
Cell Membrane Damage ◽  
Cell Counts ◽  
Extensive Cell ◽  
Fluorescence Microscopic Analysis

Wound infections are caused by bacteria and/or fungi. The presence of fungal biofilms in wound beds presents a unique challenge, as fungal biofilms may be difficult to eradicate. The goal of this work was to assess the in vitro anti-biofilm activity of a H 2 O 2 -producing electrochemical bandage (e-bandage) against 15 yeast isolates representing commonly-encountered species. Time-dependent decreases in viable biofilm CFU counts of all isolates tested were observed, resulting in no visible colonies with 48 hours of exposure by plate culture. Fluorescence microscopic analysis showed extensive cell membrane damage of biofilm cells after e-bandage treatment. Reductions in intracellular ATP levels of yeast biofilm cells were recorded post e-bandage treatment. Our results suggest that exposure to H 2 O 2 -producing e-bandages reduce in vitro viable cell counts of yeast biofilms, making this a potential new topical treatment approach for fungal wound infections.

In vitro synergistic interactions of oleanolic acid in combination with isoniazid, rifampicin or ethambutol against Mycobacterium tuberculosis

2010 ◽  
Vol 59 (5) ◽  
pp. 567-572 ◽  
Author(s):  
Fa Ge ◽  
Fanli Zeng ◽  
Siguo Liu ◽  
Na Guo ◽  
Haiqing Ye ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Oleanolic Acid ◽  
Antimycobacterial Activity ◽  
Vero Cells ◽  
Drug Resistant ◽  
Synergistic Interactions ◽  
Combination Treatments ◽  
Low Cytotoxicity ◽  
Drug Resistant Strains

Reports have shown that oleanolic acid (OA), a triterpenoid, exists widely in food, medicinal herbs and other plants, and that it has antimycobacterial activity against the Mycobacterium tuberculosis strain H37Rv (ATCC 27294). In this study it was found that OA had antimycobacterial properties against eight clinical isolates of M. tuberculosis and that the MICs of OA against drug-sensitive and drug-resistant isolates were 50–100 and 100–200 μg ml−1, respectively. The combination of OA with isoniazid (INH), rifampicin (RMP) or ethambutol (EMB) showed favourable synergistic antimycobacterial effects against six drug-resistant strains, with fractional inhibitory concentration indices of 0.121–0.347, 0.113–0.168 and 0.093–0.266, respectively. The combination treatments of OA/INH, OA/RMP and OA/EMB displayed either a synergistic interaction or did not show any interaction against two drug-sensitive strains. No antagonism resulting from the OA/INH, OA/RMP or OA/EMB combination was observed for any of the strains tested. OA exhibited a relatively low cytotoxicity in Vero cells. These results indicate that OA may serve as a promising lead compound for future antimycobacterial drug development.

scholarly journals Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance

2019 ◽  
Author(s):  
Peter Spanogiannopoulos ◽  
Patrick H. Bradley ◽  
Jonathan Melamed ◽  
Ysabella Noelle Amora Malig ◽  
Kathy N. Lam ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Drug Disposition ◽  
Transcriptional Profiling ◽  
Drug Efficacy ◽  
Drug Clearance ◽  
Gut Bacteria ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Bacterial Strains

Microbiome surveys indicate that pharmaceuticals are the top predictor of inter-individual variations in gut microbial community structure1, consistent with in vitro evidence that non-antibiotic (i.e. host-targeted) drugs inhibit gut bacterial growth2and are subject to extensive metabolism by the gut microbiome3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy5,6and toxicity7,8; however, the degree to which bacterial sensitivity and metabolism can be driven by conserved pathways also found in mammalian cells remains poorly understood. Here, we show that anticancer fluoropyrimidine drugs broadly inhibit the growth of diverse gut bacterial strains. Media supplementation, transcriptional profiling (RNA-seq), and bacterial genetics implicated pyrimidine metabolism as a key target in bacteria, as in mammalian cells. Drug resistant bacteria metabolized 5FU to its inactive metabolite dihydrofluorouracil (DHFU) mimicking the major host pathway for drug clearance. Functional orthologs of the bacterial operon responsible (preTA) are widespread across human gut bacteria from the Firmicutes and Proteobacteria phyla. The observed conservation of both the targets and pathways for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug disposition9, efficacy, and side effect profiles.

In vitro susceptibility of ceftolozane/tazobactam against typhoidal, non-typhoidal and extended spectrum β-lactamase-producing Salmonella

2021 ◽  
Author(s):  
Jade L. L. Teng ◽  
Elaine Chan ◽  
Asher C. H. Dai ◽  
Gillian Ng ◽  
Tsz Tuen Li ◽  
...  
Keyword(s):  
United States ◽  
Antimicrobial Agents ◽  
The United States ◽  
Drug Resistant ◽  
Broth Microdilution ◽  
In Vitro Susceptibility ◽  
Extended Spectrum ◽  
Control And Prevention ◽  
Esbl Producers

Both typhoidal and non-typhoidal salmonellae are included in the top 15 drug-resistant threats described by the Center for Disease Control and Prevention of the United States. There is an urgent need to look for alternative antibiotics for the treatment of Salmonella infections. We examined the in vitro susceptibilities of ceftolozane/tazobactam and six other antibiotics on typhoidal and non-typhoidal salmonellae, including isolates that are extended-spectrum β-lactamase (ESBL)-positive, using the broth microdilution test. Of the 313 (52 typhoidal and 261 non-typhoidal) Salmonella isolates tested, 98.7% were susceptible to ceftolozane/tazobactam. Based on the overall MIC 50/90 values, Salmonella isolates were more susceptible to ceftolozane/tazobactam (0.25/0.5 mg/L) compared to all other comparator agents: ampicillin (≥64/≥64 mg/L), levofloxacin (0.25/1 mg/L), azithromycin (4/16 mg/L), ceftriaxone (≤0.25/4 mg/L), chloramphenicol (8/≥64 mg/L) and trimethoprim/sulfamethoxazole (1/≥8 mg/L). When comparing the activity of the antimicrobial agents against non-typhoidal Salmonella isolates according to their serogroup, ceftolozane/tazobactam had the highest activity (100%) against Salmonella serogroups D, G, I and Q isolates, whereas the lowest activity (85.7%) was observed against serogroup E isolates. All the 10 ESBL-producing Salmonella (all non-typhoidal) isolates, of which 8 were CTX-M-55-producers and 2 were CTX-M-65-producers, were sensitive to ceftolozane/tazobactam albeit with a higher MIC 50/90 value (1/2 mg/L) than non-ESBL-producers (0.25/0.5 mg/L). In summary, our data indicate that ceftolozane/tazobactam is active against most strains of both typhoidal and non-typhoidal salmonellae and also active against ESBL-producing salmonellae.

scholarly journals NCOA4 Mediates Ferritin Responses to Iron, Erythrophagocytosis, and Hepcidin in Macrophages (P24-056-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Cole Guggisberg ◽  
Moon-Suhn Ryu
Keyword(s):  
Iron Homeostasis ◽  
Primary Source ◽  
Viable Cell ◽  
Iron Chelator ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Anemia Of Chronic Disease ◽  
Cell Counts ◽  
Subsequent Decrease

Abstract Objectives Iron recycled from erythrophagocytosis by macrophages serves as a primary source of systemic iron. NCOA4 mediates ferritin turnover via ferritinophagy. Yet, whether NCOA4 is important in macrophages or erythrophagocytosis-mediated iron recycling remains unclear, and thus was assessed in vitro. Methods J774 cells were employed as an in vitro model of macrophages. Iron studies involved treatments of ferric ammonium citrate (FAC) or an iron chelator, deferoxamine (Dfo). To recapitulate systemic iron recycling and overload, cells were treated with opsonized erythrocytes and minihepcidin, respectively. NCOA4 knock-down was achieved by siRNA transfection. Iron gene responses were measured by qPCR and western analyses, and viable cell counts were colorimetrically determined by CCK8 assays as functional outcomes. Results NCOA4 protein abundance was inversely related to iron availability and ferritin in macrophages. Loss of NCOA4 resulted in impaired ferritin turnover, and led to a reduction in viable cells when combined with iron deficiency. By erythrophagocytosis, a peak in ferritin abundance was observed at 12 h with a subsequent decrease at 24 h. This loss in ferritin was NCOA4-dependent. Minihepcidin caused accumulation of ferritin, along with a repression of NCOA4 in both control and erythrocyte-laden macrophages. Hepcidin activity had no effect on ferritin when NCOA4 was depleted. Conclusions NCOA4 mediates the release of ferritin iron during cellular iron restriction and iron recycling by macrophages. Moreover, our studies suggest that macrophage NCOA4 is integral to systemic iron homeostasis by responding to the iron regulatory hormone, hepcidin. Thus, NCOA4 and ferritinophagy may potentially serve as therapeutic targets for treatments of iron disorders and anemia of chronic disease. Funding Sources Supported by the NIFA, USDA, Hatch project under MIN-18–118 and intramural support to M-S.R.

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