Pharmacological Potential of Lathyrane-Type Diterpenoids from Phytochemical Sources

Lathyrane diterpenoids are one of the primary types of secondary metabolites present in the genus Euphorbia and one of the largest groups of diterpenes. They are characterized by having a highly oxygenated tricyclic system of 5, 11 and 3 members. These natural products and some synthetic derivatives have shown numerous interesting biological activities with clinical potential against various diseases, such as cytotoxic activity against cancer cell lines, multi-drug resistance reversal, antiviral properties, anti-inflammatory activity and their capability to induce proliferation or differentiation into neurons of neural progenitor cells. The structure of the lathyrane skeleton could be considered privileged because its framework is able to direct functional groups in a well-defined space. The favorable arrangement of these makes interaction possible with more than one target. This review aims to highlight the evidence of lathyranes as privileged structures in medicinal chemistry. Chemical structures of bioactive compounds, the evaluation of biological properties of natural and semisynthetic derivatives, and the exploration of the mechanisms of action as well as target identification and some aspects of their targeted delivery are discussed

Synthesis of Degraded Limonoid Analogs as New Antibacterial Scaffolds againstStaphylococcus aureus

Staphylococcus aureusand methicillin-resistantStaphylococcus aureus(MRSA) have become serious infections in humans and ruminants.S. aureusstrains are showing rapid changes to develop resistance in traditional antibiotic-containing systems. In the continuous fierce fight against the emergent multi-drug resistant bacterial strains, straightforward and scalable synthetic procedures to produce new active molecules are in demand. Analysis of molecular properties points to degraded limonoids as promising candidates. In this article, we report a simple synthetic approach to obtain degraded limonoid analogs as scaffolds for new antibacterial molecules. The minimum inhibitory concentrations againstS. aureuswere evaluated for the stereoisomer mixtures by the broth microdilution method. Analysis of results showed that the acetylated derivatives were the most active of them all

ISG20L2: an RNA nuclease regulating T cell activation.

ISG20L2, a 3' to 5' exoribonuclease previously associated with ribosome biogenesis, is identified here in activated T cells as an enzyme with a preferential affinity for uridylated miRNA substrates. This enzyme is upregulated in T lymphocytes upon TCR and IFN type I stimulation and appears to be involved in regulating T cell function. ISG20L2 silencing leads to an increased basal expression of CD69 and induces greater IL2 secretion. However, ISG20L2 absence impairs CD25 upregulation, CD3 synaptic accumulation and MTOC translocation towards the antigen-presenting cell during immune synapsis. Remarkably, ISG20L2 controls the expression of immunoregulatory molecules, such as AHR, NKG2D, CTLA-4, CD137, TIM-3, PD-L1 or PD-1, which show increased levels in ISG20L2 knockout T cells. The dysregulation observed in these key molecules for T cell responses support a role for this exonuclease as a novel RNA-based regulator of T cell function.This study was supported by grant P2022/BMD7209- INTEGRAMUNE from the Comunidad de Madrid, a grant from “La Caixa” Banking Foundation (HR17-00016) to FS-M; the Spanish Ministerio de Ciencia e Innovación (PDC2021-121719-I00 and PID2020-120412RB-I00 to FS-M), grant from AECC, CIBER Cardiovascular (CB16/11/00272, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015- 0505). Vaňáčová’s laboratory is supported by the Czech Science Foundation (20-19617S and 23-07372S to S.V.) and the institutional support CEITEC 2020 (LQ1601). ARG and SGD are supported by a grant from the Spanish Ministry of Universities. Funding agencies do not have intervened in the design of the studies, with no copyright over the study.S

Enteroaggregative Escherichia coli as etiological agent of endemic diarrhea in Spain: A prospective multicenter prevalence study with molecular characterization of isolates

BackgroundEnteroaggregative Escherichia coli (EAEC) is increasingly associated with domestically acquired diarrheal episodes in high-income countries, particularly among children. However, its specific role in endemic diarrhea in this setting remains under-recognized and information on molecular characteristics of such EAEC strains is limited. We aimed to investigate the occurrence of EAEC in patients with non-travel related diarrhea in Spain and molecularly characterize EAEC strains associated with illness acquired in this high-income setting.MethodsIn a prospective multicenter study, stool samples from diarrheal patients with no history of recent travel abroad (n = 1,769) were collected and processed for detection of EAEC and other diarrheagenic E. coli (DEC) pathotypes by PCR. An additional case–control study was conducted among children ≤5 years old. Whole-genome sequences (WGS) of the resulting EAEC isolates were obtained.ResultsDetection of DEC in the study population. DEC was detected in 23.2% of patients aged from 0 to 102 years, with EAEC being one of the most prevalent pathotypes (7.8%) and found in significantly more patients ≤5 years old (9.8% vs. 3.4%, p < 0.001). Although not statistically significant, EAEC was more frequent in cases than in controls. WGS-derived characterization of EAEC isolates. Sequence type (ST) 34, ST200, ST40, and ST10 were the predominant STs. O126:H27, O111:H21, and O92:H33 were the predominant serogenotypes. Evidence of a known variant of aggregative adherence fimbriae (AAF) was found in 89.2% of isolates, with AAF/V being the most frequent. Ten percent of isolates were additionally classified as presumptive extraintestinal pathogenic E. coli (ExPEC), uropathogenic E. coli (UPEC), or both, and belonged to clonal lineages that could be specifically associated with extraintestinal infections.ConclusionEAEC was the only bacterial enteric pathogen detected in a significant proportion of cases of endemic diarrhea in Spain, especially in children ≤5 years old. In particular, O126:H27-ST200, O111:H21-ST40, and O92:H33-ST34 were the most important subtypes, with all of them infecting both patients and asymptomatic individuals. Apart from this role as an enteric pathogen, a subset of these domestically acquired EAEC strains revealed an additional urinary/systemic pathogenic potential

Antibiotic use and outcome in patients with negative blood cultures, a new target population for antimicrobial stewardship interventions: A prospective multicentre cohort (NO-BACT)

[Objectives] To evaluate the appropriateness of antimicrobial treatment and the risk factors for mortality in patients with negative blood cultures (BC), in order to evaluate whether this population would be a suitable target for antimicrobial stewardship (AMS) interventions.[Methods] A multicentre prospective cohort study of patients with negative BC in three Spanish hospitals between October 2018 and July 2019 was performed. The main endpoints were the appropriateness of antimicrobial treatment (evaluated by two investigators according to local guidelines) and 30-day mortality. Cox-regression was performed to estimate the association between variables and 30-day mortality.[Results] Of 1011 patients in whom BC was obtained, these were negative in 803 (79%) and were included; 30-day mortality was 9% (70 patients); antibiotic treatment was considered inappropriate in 299 (40%) of 747 patients evaluated at day 2, and in 266 (46%) of 573 at day 5–7. The variables independently associated with increased risk of 30-day mortality were higher age (HR 1.05; 95% CI 1.03–1.07), neoplasia (HR 2.73; 95% CI 1.64–4.56), antibiotic treatment in the 48 h prior to BC extraction (HR 2.06; 95% CI 1.23–3.43) and insufficient antibiotic coverage at day 2 after BC obtainment (HR 2.35; 95% CI 1.39–4.00). Urinary, catheter and biliary sources of infection were associated with lower risk (HR 0.40; 95% CI 0.20–0.81).[Conclusions] Antimicrobial treatment is frequently inappropriate among patients with negative BC; insufficient antibiotic coverage at day 2 was associated with mortality. These results suggest that patients with negative BC are a suitable population for AS interventions.[Summary] Antimicrobial treatment in patients with negative blood culture was frequently inappropriate, and inappropriate coverage at day 2 was associated with increased risk of death. These data support the consideration of this population as a potential target for antimicrobial stewardship interventions.This study was funded by Acción Estratégica en Salud, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI17/01809), the Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001 and RD16CIII/0004/0002), the Spanish Clinical Research and Clinical Trials Platform (SCReN, PT17/0017/0012), and CIBERINFEC (CB21/13/00012, CB21/13/00087), all from Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades, and co-funded by European Development Regional Fund “A way to achieve Europe,” Operative Program Intelligence Growth 2014–2020 and ERDF/ESF, “Investing in your future.”Peer reviewe

Do specific antimicrobial stewardship interventions have an impact on carbapenem resistance in Gram-negative bacilli? A multicentre quasi-experimental ecological study: time-trend analysis and characterization of carbapenemases

CarbaPIRASOA team.[Background] Carbapenem-resistant Gram-negative bacilli (CR-GNB) are among the most threatening microorganisms worldwide and carbapenem use facilitates their spread. Antimicrobial stewardship programmes (ASPs) can help to optimize the use of antibiotics. This study evaluates the impact of a multifaceted educational ASP on carbapenem use and on the epidemiology of CR-GNB.[Methods] We conducted a quasi-experimental, time-series study in seven hospitals, from January 2014 to September 2018. The key intervention was composed of educational interviews promoting the appropriate use of carbapenems. The primary endpoints were carbapenem consumption and incidence density (ID) of CR-GNB. All non-duplicated CR-GNB clinical isolates were tested using phenotypic assays and PCR for the presence of carbapenemases. Joinpoint regression and interrupted time-series analyses were used to determine trends.[Results] A decrease in carbapenem consumption throughout the study period [average quarterly percentage change (AQPC) −1.5%, P < 0.001] and a −8.170 (−16.064 to −0.277) level change following the intervention were observed. The ID of CR-Acinetobacter baumannii decreased (AQPC −3.5%, P = 0.02) and the overall ID of CR-GNB remained stable (AQPC −0.4%, P = 0.52). CR-GNB, CR-Pseudomonas aeruginosa and CR-A. baumannii IDs per hospital correlated with the local consumption of carbapenems. The most prevalent carbapenem resistance mechanisms were OXA-23 for CR-A. baumannii (76.1%), OXA-48 for CR-Klebsiella pneumoniae (66%) and no carbapenemases for CR-P. aeruginosa (91.7%). The epidemiology of carbapenemases was heterogeneous throughout the study, especially for carbapenemase-producing Enterobacteriaceae.[Conclusions] In conclusion, a multifaceted, educational interview-based ASP targeting carbapenem prescribing reduced carbapenem use and the ID of CR-A. baumannii.This work was funded by the Spanish Infectious Diseases and Clinical Microbiology Society (SEIMC).Peer reviewe

Revisiting the epidemiology of bloodstream infections and healthcare-associated episodes: results from a multicentre prospective cohort in Spain (PRO-BAC Study)

PROBAC REIPI/GEIH-SEIMC/SAEI Group.The epidemiology of bloodstream infections (BSIs) is dynamic as it depends on microbiological, host and healthcare system factors. The aim of this study was to update the information regarding the epidemiology of BSIs in Spain considering the type of acquisition. An observational, prospective cohort study in 26 Spanish hospitals from October 2016 through March 2017 including all episodes of BSI in adults was performed. Bivariate analyses stratified by type of acquisition were performed. Multivariate analyses were performed by logistic regression. Overall, 6345 BSI episodes were included; 2510 (39.8%) were community-acquired (CA), 1661 (26.3%) were healthcare-associated (HCA) and 2056 (32.6%) hospital-acquired (HA). The 30-day mortality rates were 11.6%, 19.5% and 22.0%, respectively. The median age of patients was 71 years (interquartile range 60–81 years) and 3656 (58.3%; 95% confidence interval 57.1–59.6%) occurred in males. The proportions according to patient sex varied according to age strata. Escherichia coli (43.8%), Klebsiella spp. (8.9%), Staphylococcus aureus (8.9%) and coagulase-negative staphylococci (7.4%) were the most frequent pathogens. Multivariate analyses confirmed important differences between CA and HCA episodes, but also between HCA and HA episodes, in demographics, underlying conditions and aetiology. In conclusion, we have updated the epidemiological information regarding patients’ profiles, underlying conditions, frequency of acquisition types and aetiological agents of BSI in Spain. HCA is confirmed as a distinct type of acquisition.This work was financed by grants from Plan Nacional de I+D+i 2013–2016, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades [PI16/01432] and the Spanish Network for Research in Infectious Diseases (REIPI) [RD16/0016/0001; RD16/0016/0008], co‐financed by the European Development Regional Fund ‘A way to achieve Europe’, Operative program Intelligent Growth 2014–2020

Risk Factors and Predictive Score for Bacteremic Biliary Tract Infections Due to Enterococcus faecalis and Enterococcus faecium: a Multicenter Cohort Study from the PROBAC Project

Biliary-tract bloodstream infections (BT-BSI) caused by Enterococcus faecalis and E. faecium are associated with inappropriate empirical treatment and worse outcomes compared to other etiologies. The objective of this study was to investigate the risk factors for enterococcal BT-BSI. Patients with BT-BSI from the PROBAC cohort, including consecutive patients with BSI in 26 Spanish hospitals between October 2016 and March 2017, were selected; episodes caused by E. faecalis or E. faecium and other causes were compared. Independent predictors for enterococci were identified by logistic regression, and a predictive score was developed. Eight hundred fifty episodes of BT-BSI were included; 73 (8.5%) were due to target Enterococcus spp. (48 [66%] were E. faecium and 25 [34%] E. faecalis). By multivariate analysis, the variables independently associated with Enterococcus spp. were (OR; 95% confidence interval): cholangiocarcinoma (4.48;1.32 to 15.25), hospital acquisition (3.58;2.11 to 6.07), use of carbapenems in the previous month (3.35;1.45 to 7.78), biliary prosthesis (2.19;1.24 to 3.90), and moderate or severe chronic kidney disease (1.55;1.07 to 2.26). The AUC of the model was 0.74 [95% CI0.67 to 0.80]. A score was developed, with 7, 6, 5, 4, and 2 points for these variables, respectively, with a negative predictive value of 95% for a score # 6. A model, including cholangiocarcinoma, biliary prosthesis, hospital acquisition, previous carbapenems, and chronic kidney disease showed moderate prediction ability for enterococcal BT-BSI. Although the score will need to be validated, this information may be useful for deciding empirical therapy in biliary tract infections when bacteremia is suspected. IMPORTANCE Biliary tract infections are frequent, and a significant cause of morbidity and mortality. Bacteremia is common in these infections, particularly in the elderly and patients with cancer. Inappropriate empirical treatment has been associated with increased risk of mortality in bacteremic cholangitis, and the probability of receiving inactive empirical treatment is higher in episodes caused by enterococci. This is because many of the antimicrobial agents recommended in guidelines for biliary tract infections lack activity against these organisms. To the best of our knowledge, this is the first study analyzing the predictive factors for enterococcal BT-BSI and deriving a predictive score.8 página

The CARBA-MAP study: national mapping of carbapenemases in Spain (2014–2018)

Introduction:Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018.Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0.Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017–2018 compared to 2014–2016.Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms