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PubMed1998

A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis.

The murine multiple drug resistance (mdr) gene, mdr1a, encodes a 170-kDa transmembrane protein that is expressed in many tissues including intestinal epithelial cells, a subset of lymphoid cells and hematopoietic cells. We report that mdr1a knockout (mdr1a-/-) mice are susceptible to developing a severe, spontaneous intestinal inflammation when maintained under specific pathogen-free animal facility conditions. The intestinal inflammation seen in mdr1a-/- mice has a pathology similar to that of human inflammatory bowel disease (IBD) and is defined by dysregulated epithelial cell growth and leukocytic infiltration into the lamina propria of the large intestine. Treating mdr1a-/- mice with oral antibiotics can both prevent the development of disease and resolve active inflammation. Lymphoid cells isolated from mice with active colitis are functionally reactive to intestinal bacterial Ags, providing evidence that there is enhanced immunologic responsiveness to the normal bacterial flora during IBD. This study is the first description of spontaneous colitis in a gene knockout mouse with an apparently intact immune system. This novel model of spontaneous colitis may provide new insight into the pathogenesis of IBD, the nature of dysregulated immune reactivity to intestinal bacterial Ags, and the potential functional role of mdr genes expressed in the cells and tissues of the colonic microenvironment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2025

Genomic structure of class 1 and 2 integrons in non-typhoidal Salmonella isolated from food animals and related meat products in the USA.

OBJECTIVES: Integrons facilitate the capture and expression of exogenous genes, including antimicrobial resistance (AMR) genes. This study aimed to detect the presence of integrons, examine their genomic structure and location, and analyse integron-associated AMR, virulence and stress response genes in Salmonella using WGS. METHODS: WGS data from 193 Salmonella strains, representing 38 serotypes isolated from food animals and related meat products (2001-2019), were analysed using bioinformatic tools to assess integron presence and characterize their genomic architectures. RESULTS: Of 193 isolates, 116 (60.1%) harboured class 1 and/or class 2 integrons. Class 1 integrons alone were detected in 105 isolates, with some containing multiple copies. One S. Infantis isolate harboured only class 2 integrons, whereas 10 others contained both classes. No class 3-5 integrons were found. Twenty-seven class 1 integrons were chromosomal; the rest were plasmid-associated, linked to various plasmid incompatibility (Inc) types. Sixty-nine distinct AMR genes conferring resistance to 11 antimicrobial classes were found in integron cassettes or integron-associated plasmids. Genes linked to resistance to quaternary ammonium compounds and heavy metals, as well as ISs and transposons, were also identified. Significant virulence and stress response genes and proteins such as groES-groEL, LysR and EAL (glutamate, alanine and leucine) were common in integron cassettes. CONCLUSIONS: Class 1 integrons are prevalent in MDR Salmonella isolates from food animals and related meat products and are linked to diverse plasmid types. Their association with AMR, virulence and stress response genes underscores their role in AMR dissemination, and bacterial adaptation and pathogenicity.

Integrons↗
PubMed1996

Multidrug resistance in the world: the present situation.

Tuberculosis (TB) is the leading cause of death attributable to a single infectious pathogen with one-third of the world population infected. In the USA, TB rates have fallen 3 years in succession after a sustained rise since 1985. More important are the multidrug-resistant tuberculosis (MDR-TB) cases, which are thought to be largely due to the breakdown in the delivery of health care in the USA in conjunction with HIV infection. In countries facing the HIV epidemic, the overlap of these two populations leads to a rapid acceleration of active TB and the emergence of MDR-TB. In the USA the most recent published survey (1991) revealed that 3.5% of strains were resistant to isoniazid and rifampin. Worldwide, MDR-TB is also thought to be highly prevalent, not only because of a breakdown in health infrastructure but also because of inappropriate prescription, lack of drug availability and the use of combination capsules in which the drugs are not bioavailable. Key points in therapy are to order susceptibility tests, obtain a complete drug history, treat with an adequate number of effective drugs and never, ever add a single drug to a failing regimen.

Anti-Infective Agents↗
PubMed2000

Emerging and reemerging pathogens.

From 1973 to 1995, 29 new and reemerging pathogenic microbes were recognized. However, in discussions about emerging infectious diseases, the focus is often on the clinical effects of the host-parasite relationship, rather than the examination of the biology of the pathogen. Many of what we refer to as emerging diseases are characterized better as 'diseases of human progress'. Thus, the aerosolization of water has played an important role in the emergence of Legionella pneumophila infections. New diseases are superimposed on endemic diseases such as diarrhoeal diseases, malaria and tuberculosis. In addition, many pathogens are becoming increasingly resistant to standard antimicrobial drugs, making treatment difficult and in some cases impossible. We summarize our experience on emerging parasitic diseases (primary amoebic meningoencephalitis, respiratory cryptosporidiosis, and diplogonoporiasis), and selected problems of bacterial resistance (MDR tuberculosis caused by Mycobacterium bovis and macrolide-resistance mechanisms of Streptococcus pneumoniae and S. pyogenes).

AIDS-Related Opportunistic Infections↗
PubMed2002

Low-virulence Citrobacter species encode resistance to multiple antimicrobials.

Citrobacter spp. are gram-negative commensal bacteria that infrequently cause serious nosocomial infections in compromised hosts. They are often resistant to cephalosporins due to overexpression of their chromosomal beta-lactamase. During a recent study of multidrug-resistant Enterobacteriaceae (MDRE) in solid-organ transplant patients, we found that almost half of patients colonized with MDRE carried one or more cefpodoxime-resistant Citrobacter freundii, Citrobacter braakii, or Citrobacter amalonaticus strains. Pulsed-field gel electrophoresis showed that 36 unique strains of Citrobacter were present among 32 patients. Genetic and phenotypic analysis of the resistance mechanisms of these bacteria showed that the extended-spectrum beta-lactamase (ESBL) SHV-5 or SHV-12 was encoded by 8 strains (26%) and expressed by 7 strains (19%). A number of strains were resistant to other drug classes, including aminoglycosides (28%), trimethoprim-sulfamethoxazole (31%), and fluoroquinolones (8%). PCR and DNA analysis of these multiresistant strains revealed the presence of class I integrons, including the first integrons reported for C. braakii and C. amalonaticus. The integrons encoded aminoglycoside resistance, trimethoprim resistance, or both. Despite the prevalence of MDR Citrobacter spp. in our solid-organ transplant patients, only a single infection with a colonizing strain was recorded over 18 months. Low-virulence Citrobacter spp., which can persist in the host for long periods, could influence pathogen evolution by accumulation of genes encoding resistance to multiple antimicrobial classes.

Citrobacter↗
PubMed2006

Purification and characterization of a functionally active Mycobacterium tuberculosis prephenate dehydrogenase.

Tuberculosis (TB) remains to be a global health problem. New drugs are badly needed to drastically reduce treatment time and overcome some of the challenges with tuberculosis treatment, such as multi-drug resistant (MDR) strain infected patients or tuberculosis/HIV co-infected patients. The essentiality of mycobacterial aromatic amino acid biosynthesis pathways and their absence from human host indicate that the member enzymes of these pathways promising drug targets for therapeutic agents against pathogen mycobacteria. Prephenate dehydrogenase (PDH) is a key regulatory enzyme in tyrosine biosynthesis, catalyzing the NAD(+)-dependent conversion of prephenate to p-hydroxyphenylpyruvate, making it a potential drug target for antibiotics discovery. The recombinant PDH with an N-terminal His-tag (His-rMtPDH) was first purified in Escherichia coli, and using enterokinase rMtPDH was obtained by cleaving the N-terminal fusion partner. The effect of pH, temperature and the cation-Na(+) on purified enzyme activity was characterized. The N-terminal fusion partner was found to have little effect on the biochemical properties of PDH. We also provide in vitro evidence that Mycobacterium tuberculosis PDH does not possess any chorismate mutase (CM) activity, which suggests that, unlike many other enteric bacteria (where PDH exists as a fusion protein with CM), M. tuberculosis PDH is a monofunctional protein.

Anti-Infective Agents↗
PubMed2003

Multidrug resistant Acinetobacter baumannii isolates from a teaching hospital.

Abstract Acinetobacter baumannii is the most common nosocomial pathogen among all Acinetobacter spp. A. baumannii tend to be resistant to multiple antibiotics, and represent a severe threat in the treatment of hospitalized patients. The purpose of this study was to evaluate the prevalence, biotyping, and antibiotic resistance status of A. baumannii isolates recovered from submitted hospital clinical specimens. The in-vitro activity of 29 currently used antimicrobial agents was studied in 180 isolates of A. baumannii. The prevalence was higher in wound exudates (32%) and urine samples (22%) than in other specimens. Forty-six percent of the isolates were of biotype 9. The evolution of resistance from November 1996 through October 1998 was studied. More than 75% of the isolates were multidrug resistant (MDR) and more than 70% were #-lactamase producers. Amikacin, ampicillin + sulbactam, and imipenem are still effective antimicrobial agents, but a steady rise in the values of the minimum inhibitory concentration at which 50% of the isolates were inhibited (MIC50 )and MIC90 was observed. Resistance to aztreonam (60%), enrofloxacin (60%), imipenem (29%), moxalactam (73%), and sparfloxacin (25%) was noted; enrofloxacin and sparfloxacin are not generally used in this hospital. From the findings of the present study, no single drug appears to be suitable for empirical therapy for this nosocomial pathogen. Abstract Acinetobacter baumannii is the most common nosocomial pathogen among all Acinetobacter spp. A. baumannii tend to be resistant to multiple antibiotics, and represent a severe threat in the treatment of hospitalized patients. The purpose of this study was to evaluate the prevalence, biotyping, and antibiotic resistance status of A. baumannii isolates recovered from submitted hospital clinical specimens. The in-vitro activity of 29 currently used antimicrobial agents was studied in 180 isolates of A. baumannii. The prevalence was higher in wound exudates (32%) and urine samples (22%) than in other specimens. Forty-six percent of the isolates were of biotype 9. The evolution of resistance from November 1996 through October 1998 was studied. More than 75% of the isolates were multidrug resistant (MDR) and more than 70% were #-lactamase producers. Amikacin, ampicillin + sulbactam, and imipenem are still effective antimicrobial agents, but a steady rise in the values of the minimum inhibitory concentration at which 50% of the isolates were inhibited (MIC50) and MIC90 was observed. Resistance to aztreonam (60%), enrofloxacin (60%), imipenem (29%), moxalactam (73%), and sparfloxacin (25%) was noted; enrofloxacin and sparfloxacin are not generally used in this hospital. From the findings of the present study, no single drug appears to be suitable for empirical therapy for this nosocomial pathogen.

Acinetobacter baumannii↗
PubMed2005

Stem cell activation sustains hereditary hypertrophy in hamster cardiomyopathy.

Recent studies have documented the presence of stem cells within the myocardium and their role in the repair of ischaemic injury. Nevertheless, the pathogenic role of stem cells in non-ischaemic myocardial diseases, as well as the factors potentially responsible for their activation, is still under debate. The present study demonstrates the presence of an increased number of c-kit positive, MDR-positive, and Sca-1-positive stem cells within the myocardium of hereditary delta-SG null hamsters, a spontaneously occurring model of hypertrophic cardiomyopathy. When hamsters are 80 days old, ie at the 'hypertrophic' stage of the disease, but without haemodynamic overload, these cells associate with a multitude of cells co-expressing c-kit, cMet, GATA4, or MEF-2, and proliferating myocytes co-expressing myosin heavy chain, telomerase, ki67 and cyclin B. Furthermore, at the same animal age, the number of myocardial cells co-expressing c-kit and Flk-1, and the number of capillary vessels, is also amplified. In order to identify factors potentially responsible for stem cell activation, the myocardial expression of HGF and cMet and HGF plasma levels were evaluated, demonstrating their increase in 80-day-old delta-SG null hamsters. To demonstrate the possible ability of HGF to induce stem cell differentiation, bone-marrow-derived mesenchymal stem cells were challenged with HGF at the same plasma concentration observed in vivo. HGF induced cMet phosphorylation, and caused loss of stem cell features and overexpression of MEF-2, TEF1, and MHC. Our results demonstrate that stem cell activation occurs within the cardiomyopathic myocardium, very likely to maintain an efficient cardiac architecture. In this context, elevated levels of HGF might play a role in induction of stem cell commitment to the cardiomyocyte lineage and in cardioprotection through its anti-apoptotic action. Consistently, when cytokine levels declined to physiological concentrations, as in 150-day-old cardiomyopathic animals, myocardial apoptosis prevailed, prejudicing cardiac function.

Animals↗
PubMed2003

Emerging antibiotic resistance in urinary tract pathogens.

In vitro antimicrobial resistance is an evolving and growing problem in UTI. Much of the increase is occurring in acute uncomplicated cystitis, an infection that has traditionally been simple to treat. The current trend of rising TMP-SMX and beta-lactam resistance rates is worrisome. Of more concern, however, are the emerging issues of fluoroquinolone resistance and MDR among community-acquired urinary isolates. Judicious use of antibiotics and development of novel nonantimicrobial-based methods of prevention of UTI are important strategies to help slow the progression of resistance. In the meantime, ongoing surveillance of resistance trends and enhanced understanding of the determinants of resistance are crucial for optimal management of UTIs.

Anti-Infective Agents↗
PubMed2005

Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae.

Tigecycline is an expanded broad-spectrum antibacterial agent that is active against many clinically relevant species of bacterial pathogens, including Klebsiella pneumoniae. The majority of K. pneumoniae isolates are fully susceptible to tigecycline; however, a few strains that have decreased susceptibility have been isolated. One isolate, G340 (for which the tigecycline MIC is 4 microg/ml and which displays a multidrug resistance [MDR] phenotype), was selected for analysis of the mechanism for this decreased susceptibility by use of transposon mutagenesis with IS903phikan. A tigecycline-susceptible mutant of G340, GC7535, was obtained (tigecycline MIC, 0.25 microg/ml). Analysis of the transposon insertion mapped it to ramA, a gene that was previously identified to be involved in MDR in K. pneumoniae. For GC7535, the disruption of ramA led to a 16-fold decrease in the MIC of tigecycline and also a suppression of MDR. Trans-complementation with plasmid-borne ramA restored the original parental phenotype of decreased susceptibility to tigecycline. Northern blot analysis revealed a constitutive overexpression of ramA that correlated with an increased expression of the AcrAB transporter in G340 compared to that in tigecycline-susceptible strains. Laboratory mutants of K. pneumoniae with decreased susceptibility to tigecycline could be selected at a frequency of approximately 4 x 10(-8). These results suggest that ramA is associated with decreased tigecycline susceptibility in K. pneumoniae due to its role in the expression of the AcrAB multidrug efflux pump.

Bacterial Proteins↗
PubMed2005

Screening of some medicinal plants used in south-west Nigerian traditional medicine for anti-Salmonella typhi activity.

Ten Nigerian medicinal plants used traditionally for the treatment of several ailments of both microbial and non-microbial origins were tested on multi-drug resistant S. typhi (MDR) strains of which six of them were active. The results revealed that both the aqueous and ethanol extracts of Terminalia avicennioides, Momordica balsamina, Combretum paniculatum and Trema guineensis were effective on the MDR-S. typhi strains with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranging from 9.60 to 14 mcg/ml and 24 to 33 mcg/ml, respectively. Whereas, only the aqueous extracts of Morinda lucida and Ocimum gratissimum were found to be active against this pathogen with MIC and MBC values of 9.60 and 24 mcg/ml for M. lucida, 40 and 55 mcg/ml for O. gratissimum, respectively. There was no statistical significant difference (P > 0.05) between the activity of each plant extract and the decoctions prepared from them. All the six active plants showed positive reactions to alkaloids, tannins, flavonoids and anthraquinones but in variable degrees. All but M. balsamina, indicated the presence of saponin.

Anti-Bacterial Agents↗
PubMed2006

Efflux pumps in drug resistance of Candida.

The incidences of human pathogenic yeast Candida albicans and its related species acquiring resistance to antifungals have increased considerably, which poses serious problems towards its successful chemotherapy. The resistance of these pathogenic fungi is not restricted to the commonly used triazole compounds but is even encountered, though not often, with polyene derivatives as well. The efflux pump proteins belonging to ABC (ATP Binding Cassette) and MFS (Major Facilitators) super family are the most prominent contributors of multidrug resistance (MDR) in yeasts. The abundance of the drug transporters and their wider specificity suggest that these transporters may not be exclusively drug exporters in yeasts and may have other cellular functions. In this article we focus on some of the recent advances on the structure and function, evolution and transcriptional control of drug efflux proteins of Candida. A short discussion on the physiological relevance of drug transporters is also included.

ATP-Binding Cassette Transporters↗
PubMed2006

Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial.

In bacteria, multidrug-resistance pumps (MDRs) confer resistance to chemically unrelated amphipathic toxins. A major challenge in developing efficacious antibiotics is identifying antimicrobial compounds that are not rapidly pumped out of bacterial cells. The plant antimicrobial berberine, the active component of the medicinal plants echinacea and golden seal, is a cation that is readily extruded by bacterial MDRs, thereby rendering it relatively ineffective as a therapeutic agent. However, inhibition of MDR efflux causes a substantial increase in berberine antimicrobial activity, suggesting that berberine and potentially many other compounds could be more efficacious if an effective MDR pump inhibitor could be identified. Here we show that covalently linking berberine to INF 55 , an inhibitor of Major Facilitator MDRs, results in a highly effective antimicrobial that readily accumulates in bacteria. The hybrid molecule showed good efficacy in a Caenorhabditis elegans model of enterococcal infection, curing worms of the pathogen.

Animals↗
PubMed2000

The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.

Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.

Animals↗
PubMed2003

Baseline study to determine in vitro activities of daptomycin against gram-positive pathogens isolated in the United States in 2000-2001.

The activity of daptomycin was assessed by using 6,973 gram-positive bacteria isolated at 50 United States hospitals in 2000 and 2001. Among the isolates of Streptococcus pneumoniae (n = 1,163) collected, the rate of penicillin resistance was 16.1%; rates of oxacillin resistance among Staphylococcus aureus isolates (n = 1,018) and vancomycin resistance among Enterococcus faecium isolates (n = 368) were 30.0 and 59.5%, respectively. Multidrug-resistant (MDR) phenotypes (isolates resistant to three or more different chemical classes of antimicrobial agents) accounted for 14.2% of S. pneumoniae isolates, 27.1% of S. aureus isolates, and 58.4% of E. faecium isolates. For all gram-positive species tested, MICs at which 90% of the isolates tested were inhibited (MIC(90)s) and MIC ranges for directed-spectrum agents (daptomycin, quinupristin-dalfopristin, and linezolid) were identical or highly similar for isolates susceptible or resistant to other agents or MDR. Daptomycin had a MIC(90) of 0.12 micro g/ml for both penicillin-susceptible and -resistant isolates of S. pneumoniae. Against oxacillin-resistant S. aureus daptomycin had a MIC(90) of 0.5 micro g/ml, and it had a MIC(90) of 4 micro g/ml against both vancomycin-susceptible and -resistant E. faecium. The MIC(90)s for daptomycin and other directed-spectrum agents were unaffected by the regional or anatomical origin of isolates or patient demographic parameters (patient age, gender, and inpatient or outpatient care). Our results confirm the gram-positive spectrum of activity of daptomycin and that its activity is independent of susceptibility or resistance to commonly prescribed and tested antimicrobial agents. This study may serve as a baseline to monitor future changes in the susceptibility of gram-positive species to daptomycin following its introduction into clinical use.

Anti-Bacterial Agents↗
PubMed2003

Activity of daptomycin against susceptible and multidrug-resistant Gram-positive pathogens collected in the SECURE study (Europe) during 2000-2001.

Antibiotic resistance was prevalent in Gram-positive pathogens collected from 40 sites in 15 European countries during 2000-2001. Among Staphylococcus aureus, 27.3% of all isolates submitted were resistant to oxacillin and ranged from 0% of isolates from the Netherlands to 36.9% of isolates from Portugal. The overall prevalence of vancomycin-resistant Enterococcus faecium was 25.1%, with Italy submitting the largest percentage of resistant isolates (60.6%). For Streptococcus pneumoniae, 9.4% of all isolates collected were resistant to penicillin with variation by country from 0% in the Netherlands to 20.7% in Portugal. Multidrug resistance (MDR), defined as concurrent resistance to three or more antimicrobials of different chemical classes, was observed in 24.6% of S. aureus, 19.6% of E. faecium and 3.6% of S. pneumoniae. The directed spectrum agents daptomycin, linezolid and quinupristin-dalfopristin were active in vitro against all isolates regardless of their resistance to other agents. Daptomycin and quinupristin-dalfopristin (MIC(90)s 0.5 mg/L) were equally active against oxacillin-resistant S. aureus compared with linezolid (MIC(90) 2 mg/L). The activities of daptomycin, quinupristin-dalfopristin and linezolid were not affected by resistance to vancomycin in E. faecium (MIC(90)s of 4, 2 and 2 mg/L, respectively). Daptomycin was more active against penicillin-resistant S. pneumoniae (MIC(90) 0.25 mg/L) than was quinupristin-dalfopristin (MIC(90) 0.5 mg/L) or linezolid (MIC(90) 2 mg/L). Daptomycin was highly active against clinically important Gram-positive pathogens, including those that were multiply resistant to currently available agents. The results of this study provide a benchmark of the activity of daptomycin against contemporary European isolates and will serve as a baseline to monitor future changes in the susceptibility of these organisms to daptomycin.

Cross Infection↗
PubMed2001

Tuberculosis.

Tuberculosis is an infectious disease caused by bacteria in the Mycobacterium tuberculosis complex. Of these, the most common species to infect humans is M. tuberculosis. The TB bacillus is an extremely successful human pathogen, infecting two billion persons worldwide; an estimated 2 to 3 million people die from tuberculosis each year. In the United States, TB rates decreased steadily at the rate of 5% per year from 1953 until 1985 when the trend reversed, with the number of TB cases peaking in 1992. Outbreaks of multidrug-resistant TB (MDR TB) were reported, and these cases were documented to be transmitted in nosocomial and congregate settings, including hospitals and prisons. AIDS patients infected with M. tb developed disease rapidly, and case-fatality rates of >80% were noted in those infected with multidrug-resistant M. tb. Intensive intervention, at enormous cost, caused the number of TB cases to decline. This article discusses factors that led to the increase in TB cases, their subsequent decline, and measures needed in the future if TB is to be eliminated in the United States.

Antitubercular Agents↗