scholarly journals Potency of omadacycline against Mycobacteroides abscessus clinical isolates in vitro and in a mouse model of pulmonary infection

Author(s):  
Danielle A. Nicklas ◽  
Emily C. Maggioncalda ◽  
Elizabeth Story-Roller ◽  
Benjamin Eichelman ◽  
Chavis Tabor ◽  
...  

The incidence of nontuberculous mycobacterial diseases in the US is rising and has surpassed tuberculosis. Most notable among the nontuberculous mycobacteria is Mycobacteroides abscessus , an emerging environmental opportunistic pathogen capable of causing chronic infections. M. abscessus disease is difficult to treat and the current treatment recommendations include repurposed antibiotics, several of which are associated with undesirable side effects. In this study, we have evaluated the activity of omadacycline, a new tetracycline derivative, against M. abscessus using in vitro and in vivo approaches. Omadacycline exhibited an MIC 90 of 0.5 μg/ml against a panel of 32 contemporary M. abscessus clinical isolates several of which were resistant to antibiotics that are commonly used for treatment of M. abscessus disease. Omadacycline when combined with clarithromycin, azithromycin, cefdinir, rifabutin or linezolid also exhibited synergism against several M. abscessus strains and did not exhibit antagonism when combined with an additional nine antibiotics also commonly considered to treat M. abscessus disease. Concentration-dependent activity of omadacycline was observed in time-kill assessments. Efficacy of omadacycline was evaluated in a mouse model of lung infection against four M. abscessus strains. A dose equivalent to the 300 mg standard oral human dose was used. Compared to the untreated control group, within four weeks of treatment, 1 to 3 log 10 fewer M. abscessus colony forming units were observed in the lungs of mice treated with omadacycline. Treatment outcome was biphasic, with bactericidal activity observed after the first two weeks of treatment against all four M. abscessus strains.

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Guifeng Wang ◽  
Ning Ma ◽  
Feng He ◽  
Shosuke Kawanishi ◽  
Hatasu Kobayashi ◽  
...  

Taurine (2-aminoethane-sulfonic acid) is a type of amino acids and has numerous physiological and therapeutic functions, including anti-inflammation. However, there are few studies on the anticancer action of taurine. Our previous studies have demonstrated that taurine exhibits an apoptosis-inducing effect on human nasopharyngeal carcinoma cells in vitro. In this study, we have investigated whether taurine has an anticancer effect, using azoxymethane (AOM)/sulfate sodium (DSS)- induced mouse model for colon carcinogenesis. All mice, except those in control group, received a single intraperitoneal injection of AOM and DSS in the drinking water for 7 days twice, with 1-week interval. After the first DSS treatment, mice were given distilled water (model group) or taurine in the drinking water (taurine group) ad libitum. No tumor was observed in the control group. Taurine significantly suppressed AOM+DSS-induced tumor formation. Histopathological examination revealed AOM/DSS treatment induced colon cancer in all mice (8/8, 100%), and taurine significantly inhibited the progression of colon cancer (4/9, 44.4%). Taurine significantly attenuated cell proliferation in cancer tissues detected by Ki-67 staining. Taurine significantly increased the levels of an apoptosis marker cleaved caspase-9 and tumor suppressor protein PTEN. This is the first study that demonstrated that taurine significantly reduced carcinogenicity in vivo using AOM/DSS-induced colon cancer mouse model.


2010 ◽  
Vol 59 (3) ◽  
pp. 353-359 ◽  
Author(s):  
Abdolreza Movahedi ◽  
David J. Hampson

The anaerobic intestinal spirochaete Brachyspira pilosicoli colonizes the large intestine of humans, and various species of animals and birds, in which it may induce a mild colitis and diarrhoea. The aim of the current study was to evaluate the use of putative oligopeptide-binding proteins of B. pilosicoli as vaccine components. A partial genome sequence of B. pilosicoli porcine strain 95/1000 was subjected to bioinformatics analysis, and six genes predicted to encode oligopeptide-binding proteins were selected. Following a PCR-based distribution study of the genes across different strains of the spirochaete, they were amplified from B. pilosicoli human strain WesB and cloned in Escherichia coli. The recombinant histidine-tagged proteins were purified and subjected to in vitro and in vivo immunogenicity analysis. Recombinant products (P-1 and P-3) from two genes that were immunogenic and recognized by sera from pigs that had recovered from B. pilosicoli infections were tested in a mouse model of intestinal spirochaetosis. For each recombinant protein, groups of 12 C3H/HeJ mice were vaccinated subcutaneously with 100 μg protein emulsified in Freund's incomplete adjuvant, twice with a 2 week interval. Two weeks later the vaccinated and non-vaccinated control animals were challenged orally with B. pilosicoli strain WesB. Both proteins induced systemic and local colonic IgG antibody responses, and, following experimental infection, the cumulative number of colonization days was significantly (P<0.001) less in both groups of vaccinated mice compared to the control mice. There were significantly (P=0.012) fewer mice colonized in the group vaccinated with P-1 than in the non-vaccinated control group. The results suggest that oligopeptide-binding proteins may have potential for use as components of vaccines for B. pilosicoli.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1558-1558 ◽  
Author(s):  
Shouyun Li ◽  
Shuang Liu ◽  
Shuying Chen ◽  
Yirui Chen ◽  
Ying Wang ◽  
...  

Abstract Introduction: TBLR1-RARα is the tenth fusion gene of acute promyelocytic leukemia (APL) first identified in a rare case of APL with t(3;17)(q26;q21) chromosomal translocation in our previous study. The characteristics of its basic structure and functions had been clarified in our previous study. In this study, we successfully established a novel TBLR1-RARα leukemia mouse model (TR mouse) which fully recapitulated the most relevant features of human APLs. The therapeutic effects of retinoic acid (ATRA), arsenic trioxide (As2O3), cytarabine (Ara-C) and histone deacetylase inhibitors (HDACi) on TR mice were examined. The differentially expressed genes (DEGs) between TR mice and normal mice were compared to explore the possible mechanisms and better therapeutic targets for this kind of APL. Methods: pMSCV-TBLR1-RARα-Flag-IRES-GFP (MSCV-TR) and pMSCV-IRES-GFP (vehicle) retroviral plasmids were constructed and transfected 293T packaging cells to produce retroviruses. Lin- cells from C57BL/6 mice bone marrow were purified and infected with MSCV-TR and vehicle retroviral supernatant. For in vitro assay, the GFP+ lin- cells sorted and incubated with or without different concentrations of ATRA were analyzed for the differentiation and proliferation capacity by cell morphology, myeloid markers (CD11b and GR-1) and colony formation assay. For the in vivo experiment, GFP+ lin- cells transfected with indicated retroviral vectors were injected intravenously to lethally irradiated C57BL/6 mice to establish an APL mouse model. Cell surface markers were analyzed by flow cytometry. In treatment assays, GFP+ spleen cells from TR leukemia mice were injected intravenously into recipient mice. The mice were randomly separated into groups and received different treatment with ATRA, As2O3, As2O3 in combination with ATRA, Ara-C, Ara-C in combination with ATRA, chidamide and NL101, respectively. The percentage of GFP+ cells in peripheral blood and body weight were measured dynamically. The survival time of every group was recorded and compared. RNA-seq assay was used to identify DEGs between TR mice and normal mice. Results: In vitro assays indicated that TBLR1-RARα could either block the differentiation of HSCs at a relatively early stage or enhanced the clonogenic potential of cells. The TBLR1-RARα leukemia mouse model was successfully established. During the ten-month observational period, 3 out of 15 mice transplanted with TBLR1-RARα expressing cells developed an APL-like disease. Development of leukemia was not observed in any of the mice in control group. All the leukemia mice had a body weight loss as well as splenomegaly and hepatomegaly. The phenotype analysis revealed that the progenitor markers Sca-1, CD34 and C-kit were positive, the myeloid lineage markers Gr-1 and CD11b were also positive, erythroid lineage marker Ter119 was weekly positive, but the lymphatic lineage marker B220, CD3,CD4 and CD8 were all negative. TR mice treated with 1.5-2.5 mg/kg ATRA alone or together with 2.0 mg/kg As2O3 didn't survive longer than that of control group, although in vitro differentiation experiment showed that the leukemia cells were sensitive to ATRA. Leukemic mice receiving Ara-C treatment had a much longer survive time. Surprisingly, HDAC inhibitors (12.5 and 25 mg/kg chidamide and 30 mg/kg NL-101) could significantly prolong the survival time of TR mice. Thousands of DEGs had been identified between TR mice and wild type mice, which were widely involved in multiple pathways and participated in various biological functions. Conclusion: The TBLR1-RARα leukemia mouse model was successfully established for the first time, and its main characteristics were clarified. Although the leukemia cells were sensitive to ATRA in vitro, TR mice didn't benefit from ATRA or As2O3 treatment in vivo. Besides Ara-C, HDAC inhibitors, such as chidamide and NL-101 exhibited potency therapeutic values for TR mice, which provided a new strategy for this kind of refractory APL. What' more, lots of genes that might be related with the process of leukemogenesis and new therapeutic targets for TR leukemia were identified. This model would serve as a versatile tool to study the mechanisms of leukemogenesis and help to design better strategies for APLs in further studies. Disclosures No relevant conflicts of interest to declare.


1996 ◽  
Vol 117 (2) ◽  
pp. 267-280 ◽  
Author(s):  
M. A. Deighton ◽  
R. Borland ◽  
J. A. Capstick

SummaryThe ability to produce large quantities of bioflim on solid surfacesin vitrois believed to distinguish potentially pathogenic strains ofStaphylococcus epidermidisfrom commensals. Bioflim consists of staphylococcal cells encased in a matrix of extracellular polysaccharide (also referred to as slime), firmly adherent to each other and to the underlying surface structure. The association of slime with colonization of catheter surfacesin vivohas been examined extensively. Less attention has been paid to the contribution of slime to infections that occur in the absence of an inserted device. In a mouse model of subcutaneous infection without an implanted device 10S. epidermidisstrains (5 slime-positive, 5 slime-negative) produced abscesses; thus a foreign body is not essential for the expression of virulence byS. epidermidis. Biofilm-positive strains produced significantly more abscesses, that persisted longer than biofilm-negative strains. In these chronic infections, large numbers of staphylococci were associated with macrophages and viable staphylococci were cultured from specimens of pus collected at autopsy. Thus slime or components of slime appear to delay the clearance ofS. epidermidisfrom host tissues, possibly by interfering with intracellular killing mechanisms. However, differences in the capacity to produce abscesses, within both the slime-positive and slime-negative groups, indicate that other factors also contribute to the virulence ofS. epidermidis.


2007 ◽  
Vol 75 (8) ◽  
pp. 3715-3721 ◽  
Author(s):  
J. Andy Schaber ◽  
W. Jeffrey Triffo ◽  
Sang Jin Suh ◽  
Jeffrey W. Oliver ◽  
Mary Catherine Hastert ◽  
...  

ABSTRACT Biofilms are bacterial communities residing within a polysaccharide matrix that are associated with persistence and antibiotic resistance in chronic infections. We show that the opportunistic pathogen Pseudomonas aeruginosa forms biofilms within 8 h of infection in thermally injured mice, demonstrating that biofilms contribute to bacterial colonization in acute infections as well. Using light, electron, and confocal scanning laser microscopy, P. aeruginosa biofilms were visualized within burned tissue surrounding blood vessels and adipose cells. Although quorum sensing (QS), a bacterial signaling mechanism, coordinates differentiation of biofilms in vitro, wild-type and QS-deficient P. aeruginosa strains formed similar biofilms in vivo. Our findings demonstrate that P. aeruginosa forms biofilms on specific host tissues independently of QS.


2021 ◽  
Vol 22 (16) ◽  
pp. 8632
Author(s):  
Petra Pusic ◽  
Elisabeth Sonnleitner ◽  
Udo Bläsi

Pseudomonas aeruginosa (Pae) is an opportunistic pathogen showing a high intrinsic resistance to a wide variety of antibiotics. It causes nosocomial infections that are particularly detrimental to immunocompromised individuals and to patients suffering from cystic fibrosis. We provide a snapshot on regulatory RNAs of Pae that impact on metabolism, pathogenicity and antibiotic susceptibility. Different experimental approaches such as in silico predictions, co-purification with the RNA chaperone Hfq as well as high-throughput RNA sequencing identified several hundreds of regulatory RNA candidates in Pae. Notwithstanding, using in vitro and in vivo assays, the function of only a few has been revealed. Here, we focus on well-characterized small base-pairing RNAs, regulating specific target genes as well as on larger protein-binding RNAs that sequester and thereby modulate the activity of translational repressors. As the latter impact large gene networks governing metabolism, acute or chronic infections, these protein-binding RNAs in conjunction with their cognate proteins are regarded as global post-transcriptional regulators.


2011 ◽  
Vol 56 (3) ◽  
pp. 1215-1222 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Fiorenza Orlando ◽  
Maurizio Sanguinetti ◽  
Brunella Posteraro ◽  
Daniele Giannini ◽  
...  

ABSTRACTThe aim of this study was to compare thein vitroandin vivoactivities of micafungin, caspofungin, and anidulafungin againstCandida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against aC. glabrata-susceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains ofC. glabratawere selected:C. glabrata30, a laboratory strain harboring the mutation Fks2p-P667T, andC. glabrata51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs.In vivostudies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached.


2021 ◽  
Vol 12 ◽  
Author(s):  
Tingting Guo ◽  
Mengying Li ◽  
Xiaoli Sun ◽  
Yuhang Wang ◽  
Liying Yang ◽  
...  

Acinetobacter baumannii is an opportunistic pathogen predominantly associated with nosocomial infections. With emerging resistance against polymyxins, synergistic combinations of drugs are being investigated as a new therapeutic approach. Capsaicin is a common constituent of the human diet and is widely used in traditional alternative medicines. The present study evaluated the antibacterial activities of capsaicin in combination with colistin against three unrelated colistin-resistant Acinetobacter baumannii strains in vitro and in vivo, and then further studied their synergistic mechanisms. Using the checkerboard technique and time-kill assays, capsaicin and colistin showed a synergistic effect on colistin-resistant A. baumannii. A mouse bacteremia model confirmed the in vivo effects of capsaicin and colistin. Mechanistic studies shown that capsaicin can inhibit the biofilm formation of both colistin-resistant and non-resistant A. baumannii. In addition, capsaicin decreased the production of intracellular ATP and disrupted the outer membrane of A. baumannii. In summary, the synergy between these drugs may enable a lower concentration of colistin to be used to treat A. baumannii infection, thereby reducing the dose-dependent side effects. Hence, capsaicin–colistin combination therapy may offer a new treatment option for the control of A. baumannii infection.


2017 ◽  
Author(s):  
Alana Schick ◽  
Rees Kassen

AbstractChronic infection of the cystic fibrosis (CF) airway by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality for adult CF patients. Prolonged infections are accompanied by adaptation of P. aeruginosa to the unique conditions of the CF lung environment as well as marked diversification of the pathogen into phenotypically and genetically distinct strains that can coexist for years within a patient. Little is known, however, about the causes of this diversification and its impact on patient health. Here, we show experimentally that, consistent with ecological theory of diversification, the nutritional conditions of the CF airway can cause rapid and extensive diversification of P. aeruginosa. The increased viscosity associated with the thick mucous layer in the CF airway had little impact on within-population diversification but did promote divergence among populations. Notably, in vitro evolution recapitulated patho-adaptive traits thought to be hallmarks of chronic infection, including reduced motility and increased biofilm formation, and the range of phenotypes observed in a collection of clinical isolates. Our results suggest that nutritional complexity and reduced dispersal can drive evolutionary diversification of P. aeruginosa independent of other features of the CF lung such as an active immune system or the presence of competing microbial species. They also underscore the need to obtain diverse samples of P. aeruginosa when developing treatment plans. We suggest that diversification, by generating extensive phenotypic and genetic variation on which selection can act, may be a key first step in the transition from transient to chronic infection.Significance StatementChronic infection with the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of lung transplant or death in cystic fibrosis patients. P. aeruginosa diversifies in the CF lung, although why this happens remains a mystery. We allowed P. aeruginosa to evolve in the laboratory under a range of conditions approximating the CF lung. The diversity of evolved populations was highest, and most closely resembled the range of phenotypes among clinical isolates, in environments resembling the spectrum of nutritional resources available in the CF lung. Our results point to the nutritional complexity of the CF lung as a major driver of diversification and they suggest that diversity could be important in the development of chronic infections.


2004 ◽  
Vol 70 (1) ◽  
pp. 518-526 ◽  
Author(s):  
D. Sgouras ◽  
P. Maragkoudakis ◽  
K. Petraki ◽  
B. Martinez-Gonzalez ◽  
E. Eriotou ◽  
...  

ABSTRACT We studied the potential inhibitory effect of Lactobacillus casei strain Shirota (from the fermented milk product Yakult [Yakult Ltd., Tokyo, Japan]) on Helicobacter pylori by using (i) in vitro inhibition assays with H. pylori SS1 (Sydney strain 1) and nine H. pylori clinical isolates and (ii) the in vivo H. pylori SS1 mouse model of infection over a period of 9 months. In vitro activity against H. pylori SS1 and all of the clinical isolates was observed in the presence of viable L. casei strain Shirota cells but not in the cell-free culture supernatant, although there was profound inhibition of urease activity. In vivo experiments were performed by oral administration of L. casei strain Shirota in the water supply over a period of 9 months to 6-week-old C57BL/6 mice previously infected with H. pylori SS1 (study group; n = 25). Appropriate control groups of H. pylori-infected but untreated animals (n = 25) and uninfected animals given L. casei strain Shirota (n = 25) also were included in the study. H. pylori colonization and development of gastritis were assessed at 1, 2, 3, 6, and 9 months postinfection. A significant reduction in the levels of H. pylori colonization was observed in the antrum and body mucosa in vivo in the lactobacillus-treated study group, as assessed by viable cultures, compared to the levels in the H. pylori-infected control group. This reduction was accompanied by a significant decline in the associated chronic and active gastric mucosal inflammation observed at each time point throughout the observation period. A trend toward a decrease in the anti-H. pylori immunoglobulin G response was measured in the serum of the animals treated with lactobacillus, although this decrease was not significant.


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