Hemoglobin degradation is a metabolic process that is central to the growth and maturation of the malaria parasite Plasmodium falciparum. Two aspartic proteases that initiate degradation, plasmepsins (PMs) I and II, have been identified and extensively characterized. Eight additional PM genes are present in the P. falciparum genome. To better understand the enzymology of hemoglobin degradation, it is necessary to determine which of these genes are expressed when hemoglobin degradation is occurring, which encode active enzymes, and which gene products are found in the food vacuole where catabolism takes place. Our genome-wide analysis reveals that PM I, II, and IV and histoaspartic protease encode hemoglobin-degrading food vacuole proteases. Despite having a histidine in place of one of the catalytic aspartic acids conserved in other aspartic proteases, histo-aspartic protease is an active hydrolase.
E scherichia coli sequence type 131 (ST131) is a recently emerged, extensively antimicrobial-resistant E. coli clonal group that has spread explosively throughout the world, driving the rapid increase in prevalence of antimicrobial resistance in E. coli (1-5). Such widespread expansion of a single clonal group is unprecedented in E. coli populations, although it has been seen in other antimicrobial-resistant pathogens such as methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and the NAP1 strain of Clostridium difficile (6, 7), and was foreshadowed by the notorious but less extensive expansion of E. coli "clonal group A" (8-10). Despite ST131 being recognized as a pandemic clonal group that threatens public health, ST131 has received comparatively less attention in the United States than have other antimicrobial-resistant pathogens. Here we review the epidemiology and molecular phylogeny of ST131, possible mechanisms for its ecological success, and implications of its widespread dissemination. EARLY STUDIES OF ST131 EPIDEMIOLOGY AND RESISTANCEST131, which is defined by the sequences of the 7 housekeeping genes that are commonly used for multilocus sequence typing (MLST) in E. coli according to the Achtman MLST scheme (http: //mlst.warwick.ac.uk/mlst/dbs/Ecoli), was first reported in 2008 by two research groups that were studying CTX-M-type extended-spectrum-beta-lactamase (ESBL)-producing E. coli (2, 11). By 2009, ST131 had been identified in 9 countries spanning 3 continents (3-5). ST131 belongs to (virulence-associated) E. coli phylogenetic group B2, and most isolates exhibit serotype O25b:H4, except for a small subset that are serotype O16:H5 (12) and rare variants with other serotypes (13). ST131 is associated with distinct combinations of extraintestinal virulence factors, compared with non-ST131 E. coli (4,(14)(15)(16)(17), and exhibits diverse pulsedfield gel electrophoresis (PFGE) profiles, several of which predominate globally (18).According to recent studies, the prevalence of ST131 among human clinical E. coli isolates varies by geographic region and host population, ranging overall from 12.5% (19) to nearly 30% (15, 20, 21) of E. coli clinical isolates. Like other extraintestinal pathogenic E. coli (ExPEC) strains, ST131 causes a variety of extraintestinal infections, including bacteremia, pneumonia, and urinary tract, intra-abdominal, and wound infections. Whether ST131 is associated with worse clinical outcomes than other E. coli strains is unclear, since some studies suggest that ST131 is more likely to cause persistent or recurrent urinary tract infections (20) or a higher frequency of sepsis (22), whereas others have found no difference in outcomes of infections with ST131 versus other E. coli strains (23, 24). In one study, patients infected with ST131 had persistent or recurrent symptoms in part because they received empirical therapy with fluoroquinolones (FQs), which are ineffective against most members of this clonal group (20).Regarding epidemiologi...
OBJECTIVE To determine prevalence, predictors, and outcomes of infection due to Escherichia coli sequence type ST131. DESIGN Retrospective cohort. SETTING All healthcare settings in Olmsted County, Minnesota (eg, community hospital, tertiary care center, long-term care facilities, and ambulatory clinics). PATIENTS Ambulatory and hospitalized children and adults with extraintestinal E. coli isolates. METHODS We analyzed 299 consecutive, nonduplicate extraintestinal E. coli isolates submitted to Olmsted County laboratories in February and March 2011. ST131 was identified using single-nucleotide polymorphism polymerase chain reaction and further evaluated through pulsed-field gel electrophoresis. Associated clinical data were abstracted through medical record review. RESULTS Most isolates were from urine specimens (90%), outpatients (68%), and community-associated infections (61%). ST131 accounted for 27% of isolates overall and for a larger proportion of those isolates resistant to fluoroquinolones (81%), trimethoprim-sulfamethoxazole (42%), gentamicin (79%), and ceftriaxone (50%). The prevalence of ST131 increased with age (accounting for 5% of isolates from those 11–20 years of age, 26% of isolates from those 51–60 years of age, and 50% of isolates from those 91–100 years of age). ST131 accounted for a greater proportion of healthcare-associated isolates (49%) than community-associated isolates (15%) and for fully 76% of E. coli isolates from long-term care facility (LTCF) residents. Multivariable predictors of ST131 carriage included older age, LTCF residence, previous urinary tract infection, high-complexity infection, and previous use of fluoroquinolones, macrolides, and extended-spectrum cephalosporins. With multivariable adjustment, ST131-associated infection outcomes included receipt of more than 1 antibiotic (odds ratio [OR], 2.54 [95% confidence interval (CI), 1.25–5.17]) and persistent or recurrent symptoms (OR, 2.53 [95% CI, 1.08–5.96]). Two globally predominant ST131 pulsotypes accounted for 45% of ST131 isolates. CONCLUSIONS ST131 is a dominant, antimicrobial-resistant clonal group associated with healthcare settings, elderly hosts, and persistent or recurrent symptoms.
fWe assessed Escherichia coli ST131 and its H30 and H30-Rx subclones for virulence genes, antimicrobial resistance, and extended-spectrum beta-lactamase (ESBL) type. Although both subclones were associated with ESBL production, H30-Rx isolates had higher resistance scores and were associated specifically with CTX-M-15. Three virulence genes (iha, sat, and iutA) were more prevalent among H30 than non-H30 ST131 isolates. Thus, the H30 and H30-Rx subclones are more antimicrobial resistant and have virulence profiles that are distinct from those of non-H30 ST131 isolates.T he H30 and H30-Rx subclones of Escherichia coli sequence type 131 (ST131) have expanded more extensively than other ST131 variants, for as-yet-unexplained reasons. The H30 subclone, so named because it contains allele 30 of fimH (type 1 fimbrial adhesin gene), comprises almost all current fluoroquinolone-resistant ST131 isolates (1). Within the H30 subclone, the H30-Rx subset often carries bla CTX-M-15 and may constitute its main repository within ST131 (2). Here we determined the prevalence of ST131 and its H30 and H30-Rx subclones among isolates from a case-control study of infections caused by extended-spectrum--lactamase (ESBL)-producing E. coli strains (3) and compared these groups for virulence genotypes, antimicrobial resistance, and ESBL type.A total of 267 (100 ESBL-positive and 167 ESBL-negative) E. coli isolates were collected prospectively between 2007 and 2010 for a case-control study, as described in detail elsewhere (3), with approval by the NorthShore and VA Medical Center institutional review boards. Fifteen health care-associated isolates, collected during the prospective study Ͼ2 days after hospital admission, were excluded from the study reported in reference 3 but were evaluated here. Established PCR-based methods were used to define E. coli phylogenetic group (A, B1, B2, and D) (4), ST131 and its H30 subclone (1, 2, 5), major CTX-M groups (6), the presence of bla CTX-M-15 (7), and extended virulence genotypes (8-10). The H30-Rx subclone was identified by PCR detection of a specific single-nucleotide polymorphism (SNP) (G723A) within the allantoin-encoding gene, ybbW (2). Primers APfor63 (5=-GGTTGC GGTCTGGGCA-3=) and APrev66 (5=-CAATATCCAGCACGTT CCAGGTG-3=), with a cycling routine of 95°C for 8 min, 31 cycles of 94°C for 20 s and 72°C for 40 s, and a final extension at 72°C (for 5=), yielded a 194-bp amplicon. The resistance score was the total
DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.
During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo, despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N-acetyl-L-leucyl-L-leucyl-norleucinal and N-acetyl-L-leucyl-L-leucyl-methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo, but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.Nearly half the world's population lives in malaria endemic areas. Every year several hundred million people are afflicted and over two million people die from this disease, mainly children (1). Malaria is increasing as a global problem because parasites have developed resistance to drugs used for prophylaxis and treatment at an alarming rate. Thus, there is an urgent need to identify new drug targets (2). Plasmodium falciparum, the organism responsible for the most lethal form of malaria, is an obligate intracellular parasite that resides for most of the course of infection in the host erythrocyte. Hemoglobin degradation is essential for the survival of the parasite and agents that disrupt the hemoglobin catabolic pathway are considered good prospects for antimalarial chemotherapy (3).During the organism's trophozoite stage most of the host cell hemoglobin is degraded (4 -6), supplying the parasite with amino acids for protein synthesis and energy metabolism (7). Plasmodium ingests hemoglobin by means of the cytostome, an invagination that spans the parasite plasma membrane and the parasitophorous vacuolar membrane (a red cell-derived structure with which the parasite surrounds itself as it invades). The cytostome fills with host cell cytoplasm and pinches off to form transport vesicles. These double membrane...
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